Effect of CSL112 on Recurrent Myocardial Infarction and Cardiovascular Death: Insights from the AEGIS-II Trial.

BACKGROUND: The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI. OBJECTIVES: This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of CV death and recurrent MI. METHODS: The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6g CSL112) or placebo. RESULTS: The incidence of the composite of cardiovascular death and type 1 MI was 11-16% lower in the CSL112 group over the study period (HR of 0.84 [95% CI 0.7-1.0; p=0.056] day 90, HR 0.86, [95% CI 0.74-0.99; p=0.048] day 180, and HR 0.89, [95% CI 0.79-1.01 p=0.07; p=0.07] day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112 treated patients throughout the follow-up period (HR 0.92 [95% CI 0.8-1.05], 0.89 [95% CI 0.79-0.996], 0.91 [0.82-1.01]. The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis). CONCLUSION: While CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared to placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations.

Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

BACKGROUND: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear. METHODS: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up. RESULTS: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group. CONCLUSIONS: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial.

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.

Impact of age on the predictive value of NT-proBNP in patients with diabetes mellitus stabilised after an acute coronary syndrome.

AIMS: To assess the impact of age on the prognostic value of NT-proBNP concentration in patients with type-2 diabetes mellitus (T2DM) stabilised after an Acute Coronary Syndrome (ACS). METHODS: The AleCardio study compared aleglitazar with placebo in 7226 patients with T2DM and recent ACS. Patients with heart failure were excluded. Median follow-up was 104 weeks. Baseline NT-proBNP plasma concentration was measured centrally. Multivariable Cox regression was used to determine the mortality predictive information provided by NT-proBNP across age groups. RESULTS: Median age was 61y (IQR 54, 67). NT-proBNP concentration increased by quartile (Q) of age (median 264, 318, 391, and 588 pg/ml). Compared to Q1, patients in Q4 of NT-proBNP had higher (p < 0.001) adjusted HR for all-cause (aHR 6.9; 95 % CI 4.0-12) and cardiovascular (11; 5.4-23) death. Within each age Q, baseline NT-proBNP in patients who died was 3 times higher than in survivors (all p < 0.001). When age and NT-proBNP levels were modeled as continuous variables, their interaction term was nonsignificant. The relative prognostic information provided by NT-proBNP (percent of total X2) increased from 38 % in age Q1 to 75 % in age Q4 for mortality, and from 50 % to 88 % for CV death. CONCLUSIONS: Among patients with T2DM stabilised after an ACS, NT-proBNP level predicts death irrespective of age.

Trends and Outcomes Associated With Bariatric Surgery and Pharmacotherapies With Weight Loss Effects Among Patients With Heart Failure and Obesity.

BACKGROUND: Utilization patterns of bariatric surgery among older patients with heart failure (HF), and the associations with cardiovascular outcomes, are not well known. METHODS: Medicare beneficiaries with HF and at least class II obesity from 2013 to 2020 were identified with Medicare Provider Analysis and Review 100% inpatient files and Medicare 5% outpatient files. Patients who underwent bariatric surgery were matched to controls in a 1:2 ratio (matched on exact age, sex, race, body mass index, HF encounter year, and HF hospitalization rate pre-surgery/matched period). In an exploratory analysis, patients prescribed pharmacotherapies with weight loss effects (semaglutide, liraglutide, naltrexone-bupropion, or orlistat) were identified and matched to controls with a similar strategy in addition to HF medical therapy data. Cox models evaluated associations between weight loss therapies (as a time-varying covariate) and mortality risk and HF hospitalization rate (calculated as the rate of HF hospitalizations following index HF encounter per 100 person-months) during follow-up. RESULTS: Of 298 101 patients with HF and body mass index ≥35 kg/m2, 2594 (0.9%) underwent bariatric surgery (45% men; mean age, 56.2 years; mean body mass index, 51.5 kg/m2). In propensity-matched analyses over a median follow-up of 4.7 years, bariatric surgery was associated with lower risk of all-cause mortality (HR, 0.55 [95% CI, 0.49-0.63]; P<0.001), greater reduction in HF hospitalization rate (rate ratio, 0.72 [95% CI, 0.67-0.77]; P<0.001), and lower atrial fibrillation risk (HR, 0.78 [95% CI, 0.65-0.93]; P=0.006). Use of pharmacotherapies with weight loss effects was low (4.8%), with 96.3% prescribed GLP-1 (glucagon-like peptide-1) agonists (semaglutide, 23.6%; liraglutide, 72.7%). In propensity-matched analysis over a median follow-up of 2.8 years, patients receiving pharmacotherapies with weight loss effects (versus matched controls) had a lower risk of all-cause mortality (HR, 0.82 [95% CI, 0.71-0.95]; P=0.007) and HF hospitalization rate (rate ratio, 0.87 [95% CI, 0.77-0.99]; P=0.04). CONCLUSIONS: Bariatric surgery and pharmacotherapies with weight loss effects are associated with a lower risk of adverse outcomes among older patients with HF and obesity; however, overall utilization remains low.

Coronary spasm and vasomotor dysfunction as a cause of MINOCA.

Increasing evidence has shown that coronary spasm and vasomotor dysfunction may be the underlying cause in more than half of myocardial infarctions with non-obstructive coronary arteries (MINOCA) as well as an important cause of chronic chest pain in the outpatient setting. We review the contemporary understanding of coronary spasm and related vasomotor dysfunction of the coronary arteries, the pathophysiology and prognosis, and current and emerging approaches to diagnosis and evidence-based treatment.

Implementing a comprehensive STEMI protocol to improve care metrics and outcomes in patients with in-hospital STEMI: an observational cohort study.

BACKGROUND: Patients who experience in-hospital ST-segment elevation myocardial infarction (iSTEMI) represent a uniquely high-risk cohort owing to delays in diagnosis, prolonged time to reperfusion and increased mortality. Quality initiatives aimed at improving the care of this vulnerable, yet understudied population are needed. METHODS: This study included consecutive patients with iSTEMI treated with percutaneous coronary intervention (PCI) between 1 January 2011 and 15 July 2019 at a single, tertiary referral centre. A comprehensive iSTEMI protocol (CSP) was implemented on 15 July 2014, incorporating: (1) cardiology fellow activation of the catheterisation lab using standardised criteria, (2) nursing chest pain protocol, (3) improved electronic access to electrocardiographic studies, (4) checklist for initial triage and management, (5) 24/7/365 catheterisation lab readiness and (6) radial-first PCI approach. Key metrics and clinical outcomes were compared before and after CSP implementation. RESULTS: Among 125 total subjects, the post-CSP cohort (n=81) was younger, had more males and were more likely to be hospitalised for cardiac-related reasons relative to the pre-CSP cohort (n=44) who were more likely hospitalised for operative-related aetiologies. After CSP adoption, median ECG-to-first-device-activation time decreased from 113 min to 64 min (p<0.001), goal ECG-to-first-device-activation time increased from 36% to 76% of patients (p<0.001), administration of guideline-directed medical therapy prior to PCI increased from 27.3% to 65.4% (p<0.001), trans-radial access increased from 16% to 70% (p<0.001) and rates of discharge home increased from 56.8% to 76.5% (p=0.04). Statistically insignificant numerical reductions were observed post-CSP in in-hospital mortality (18.2% vs 9.9%, p=0.30), 30-day mortality (15.9% vs 12.3%, p=0.78) and 1-year mortality (27.3% vs 21.0%, p=0.57). CONCLUSIONS: The implementation of a CSP was associated with marked enhancements in key care metrics among patients with iSTEMI. Among a larger cohort, the use of a CSP yielded a significant reduction in ECG-to-first-device-activation time in a particularly vulnerable population at high risk of death.

Depressive Syndromes in Men with Hypogonadism in the TRAVERSE Trial: Response to Testosterone Replacement Therapy.

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. DESIGN: Randomized, placebo-controlled, double-blind. SETTING: 316 trial sites. PARTICIPANTS: Men, 45 to 80 years, with two fasting testosterone levels <300 ng/dL, one or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated three 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 randomized men. INTERVENTION: 1.62% transdermal testosterone or placebo gel. OUTCOME MEASURES: Proportions of participants 1) meeting criteria for LG-PDD or 2) with significant depressive symptoms; changes in depressive symptoms, energy, sleep quality, and cognition in testosterone- vs. placebo-treated men in the three subgroups. RESULTS: Of 5,204 randomized participants, 2,643 (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 randomized participants (n=5204), TRT was associated with modest but significantly greater improvements in mood and energy but not cognition or sleep quality. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03518034.

Impact of Bempedoic Acid on Total Cardiovascular Events: A Prespecified Analysis of the CLEAR Outcomes Randomized Clinical Trial.

Importance: The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown. Objective: To determine the impact of bempedoic acid on the total incidence of MACE. Design, Setting, and Participants: Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022. Interventions: Patients were randomly assigned to treatment with bempedoic acid or placebo daily. Main Outcomes and Measures: The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups. Results: A total of 13 970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients. Conclusion and Relevance: Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.

Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial.

BACKGROUND: Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of major adverse cardiovascular events among statin-intolerant patients at high cardiovascular risk. In this prespecified analysis, our dual aims were to evaluate the cardiovascular benefits of bempedoic acid, an ATP-citrate lyase inhibitor, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA1c among those without diabetes in the CLEAR Outcomes trial. METHODS: CLEAR Outcomes was a randomised, double-blind, placebo-controlled trial conducted across 1250 primary care and outpatient sites in 32 countries. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo. In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status. The prespecified analysis of risk of new-onset diabetes and HbA1c increase was evaluated in patients without diabetes at baseline. The CLEAR Outcomes trial was completed on Nov 7, 2022, and is registered with ClinicalTrials.gov (NCT02993406). FINDINGS: Between Dec 22, 2016, and Nov 7, 2022, 13 970 patients were screened and randomly assigned; 6373 (45·6%) with diabetes, 5796 (41·5%) with prediabetes, and 1801 (12·9%) with normoglycaemia. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid (HR 0·83; 95% CI 0·72-0·95; absolute risk reduction of 2·4%) compared to placebo, with no statistical evidence of effect modification across glycaemic strata (interaction p=0·42). The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups, with 429 of 3848 (11·1%) with bempedoic acid versus 433 of 3749 (11·5%) with placebo (HR 0·95; 95% CI 0·83-1·09). HbA1c concentrations at month 12 and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabtes, and normoglycaemia) for patients randomly assigned to bempedoic acid (all p<0·001). INTERPRETATION: Among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes. FUNDING: Esperion Therapeutics.

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

BACKGROUND: Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. METHODS: The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. RESULTS: Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. CONCLUSIONS: Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.

Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism.

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.

Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics.

BACKGROUND: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial. METHODS: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis). RESULTS: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m2. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing. CONCLUSION: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.

Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial.

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 14 304 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.

Safety of bempedoic acid in patients at high cardiovascular risk and with statin intolerance.

BACKGROUND: Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins. OBJECTIVE: To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies. METHODS: CLEAR Outcomes was a double-blind trial conducted in 13,970 patients randomized to oral bempedoic acid 180 mg daily or placebo and followed for a median of 3.4 years. RESULTS: In patients who received at least one dose (7,001 bempedoic acid, 6,964 placebo), treatment emergent adverse events (AE) occurred in 86.3 % and 85 % of patients, respectively. COVID-19 was the most frequently reported AE in both groups. Changes in serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid were consistent with the known safety profile of bempedoic acid. Gout or gouty arthritis occurred in 3.2 % of bempedoic acid and 2.2 % of placebo patients. AE associated with tendinopathies, including tendon rupture, occurred in 2 % of patients in both treatment groups. Cholelithiasis occurred in 2.2 % of bempedoic acid and 1.2 % of placebo patients; AE related to gallbladder disease were similar between treatment groups. CONCLUSIONS: Bempedoic acid was well-tolerated compared with placebo. Safety data from the long-term CLEAR Outcomes study reinforce the positive benefit-risk profile of bempedoic acid.