Month: November 2023

(UroToday.com) The 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28th and December 1st, 2023, was host to a prostate cancer course. Dr. Alicia Morgans discussed the cardiac morbidity of androgen receptor (AR) agonists, compared to AR antagonists. There are two broad categories of androgen deprivation therapy (ADT) to suppress testosterone levels: Surgical castration: Bilateral orchiectomy Medical castration, using either: Gonadotropin-releasing hormone (GnRH) receptor agonists GnRH agonists compete with GnRH produced in the hypothalamus and bind to receptors in the pituitary. This ultimately leads to a downregulation of the production of LH and testosterone. They are typically associated with an initial flare that usually lasts for approximately one week. GnRH receptor antagonists It is important to remember that hormonal therapy for prostate cancer lowers both testosterone and estrogen levels, which has many physiologic sequelae. How do GnRH receptor agonists and antagonists differ? As summarized in the table below, GnRH antagonists are associated with a much shorter time to castration (96 hours versus 3 to 4 weeks), do not lead to a testosterone flare, and may have lower PSA failure rates. This comes at the ‘cost’ of increased frequency of local injection site reactions (40% versus 1%) and the requirement for monthly injections or daily oral pills, versus intramuscular/subcutaneous injections every three months with GnRH agonists.While all GnRH agonists are equally effective for cancer control, GnRH antagonists may be useful in patients who require rapid reduction of testosterone levels (e.g., patients with severe symptoms or with impending emergencies – spinal-cord compression with impending paraplegia, severe bone pain, or bladder outlet obstruction). While there remains some debate as to whether GnRH antagonists have a more favorable cardiovascular safety profile compared to GnRH agonists, what is clear is that all ADT negatively impacts cardiovascular risk factors. ADT increases total cholesterol levels, triglyceride levels, and abdominal adipose tissue and impairs glucose metabolism.1 Medical complications occur in men because of both low testosterone and low estradiol levels. Many people think of ADT as causing “male menopause” because of the associated hot flashes and changes in mood/libido. However, it is clear that the complications of ADT can significantly impact morbidity and mortality in this population. The potential mechanisms of ADT-associated increased cardiovascular risk may differ from agonists to antagonists, with the following underlying mechanisms proposed: Local inflammation via activation of T cells caused by GnRH agonists triggering plaque destabilization and rupture Pro-inflammatory effects of Follicle Stimulating Hormone (FSH) and FSH-mediated alterations in adipocyte composition and adipokine release, inducing cardiometabolic changes Cardioprotection provided by testosterone interrupted by ADT (both forms) In 2014, Albertsen et al. demonstrated that degarelix (GnRH antagonist) was associated with a lower cardiovascular risk, compared to GnRH agonists, in a cohort of patients with a history of cardiovascular disease (~30%). As demonstrated in the Kaplan Meier curve below, patients receiving degarelix had a significantly lower rate of severe cardiovascular events or death (HR: 0.44, 95% CI: 0.26 – 0.74).2 These results have been similarly corroborated by Margel et al. who demonstrated in an open-label, phase 2 trial that GnRH antagonists were associated with lower risk of cardiovascular events or major cardiovascular and cerebrovascular events.3A subsequent systematic review and meta-analysis demonstrated that there was a significant reduction in both cardiovascular events and cardiovascular death with GRH antagonists, compared to GnRH agonists.4In 2020, the phase 3 HERO trial of relugolix (oral GnRH antagonist) versus leuprolide (GnRH agonist) was published in The New England Journal of Medicine. This was a multinational, phase III, randomized, open-label, parallel-group study to evaluate the safety and efficacy of relugolix in men with advanced prostate cancer. The primary endpoint was sustained castration through 48 weeks, defined as <50 ng/dL.Notably, 93% of patients in this trial had pre-existing cardiovascular risk factors.Of men who received relugolix, 97% maintained castration through 48 weeks, as compared with 89% of men receiving leuprolide. The difference of 7.9 percentage points (95% CI: 4.1 to 11.8) showed both the non-inferiority and superiority of relugolix (p<0.001 for superiority).Significantly, patients in the relugolix arm had a 54% reduction in the risk of major adverse cardiovascular events.This benefit was most pronounced in patients with a history of a prior major adverse cardiovascular event (3.6% versus 17.8%).5In 2021, results of the PRONOUNCE randomized trial comparing the cardiovascular safety of degarelix versus leuprolide in patients with prostate cancer were published. No significant differences were observed between patients treated with degarelix (5.5%) versus leuprolide (4.1%; HR: 1.28, 95% CI: 0.59 – 2.79, p=0.53). However, there were several significant limitations to this trial. The recruitment was slower than originally planned, with the primary outcome event rate lower than expected. The sponsor closed enrollment with 545 of the planned 900 participants recruited.The RADICAL PC study prospectively characterized 2,492 consecutive men (mean age 68 years) with prostate cancer (newly diagnosed or with a plan to ADT for the first time) from 16 Canadian sites. Cardiovascular risk was estimated by calculating Framingham risk scores. Most (58%) were current or former smokers, 22% had known cardiovascular disease, 16% diabetes, 45% hypertension, 31% body mass index 30 kg/m2 or greater, and 24% had low levels of physical activity. Interestingly, patients with more cardiovascular risk factors were more likely to receive ADT in this study. This may have been driven by greater age and lower socioeconomic status in the group with higher risk prostate cancer who were planned to get ADT.6 The NCCN guidelines currently recommend the ‘ABCDE’ systematic approach to addressing cardiovascular risk factors in cancer patients, as summarized below:Dr. Morgans concluded her presentation with the following take home messages: Pharmacologic ADT can be delivered as GnRH agonist or antagonist therapy Differences between these include mode of administration and testosterone flare, but disease control is similar ADT negatively affects cardiovascular risk factors and is likely associated with risk of cardiovascular events GnRH antagonists may be associated with lower risk of cardiovascular events when compared with GnRH agonists Systematic management of cardiovascular risk factors is a recommended approach to providing optimal cardiovascular care for patients

GLP-1 agonists such as semaglutide and liraglutide can help patients with type 2 diabetes improve their blood sugar levels, lose weight and even improve their overall cardiovascular health. But these drugs are often taken as daily or weekly injections, meaning there is an inherent risk that adherence will suffer as time goes on. This could make the therapies less effective and cause patients to grow frustrated. According to a new study published in Cell Reports Medicine, however, those patients could potentially be taking GLP-1 agonists much less frequently in the future.[1] A team of specialists out of Stanford University have developed a new injectable hydrogel drug delivery system that helps medications slowly dissipate over time as opposed to hitting the patient all at once. This means a drug such as semaglutide could potentially be injected just once every four months and still have the same clinical impact it would have being injected weekly. “Adherence is one of the biggest challenges in type 2 diabetes management,” senior author Eric Appel, PhD, associate professor of materials science and engineering at Stanford, said in a prepared statement. “Needing only three shots a year would make it much easier for people with diabetes or obesity to stick with their drug regimens.” Appel et al. tested their new hydrogel on laboratory rats, finding significant success. Testing the new drug delivery system on pigs is the team’s next step, and then they hope they can start planning human trials. “At the very least, we have laid a pathway for the prolonged release of therapeutic GLP-1–based anti-diabetic and anti-obesity treatments that could have beneficial impact on type 2 diabetes management and, perhaps, other conditions as well,” Appel said in the same statement.

quitting smoking broken cigarette: © mbruxelle – stock.adobe.com Patients who quit smoking cut their risks of heart, cancer and lung death over time. A new study aimed to measure the decrease in cause-specific mortality among former smokers, based on years since quitting. Examining data from 438,015 American adults, researchers Blake Thomson, DPhil, and Farhad Islami, MD, PhD, analyzed characteristics 11,860 cardiovascular deaths, 10,935 cancer deaths, and 2,060 respiratory deaths over 5 million per-years of follow-up. Within 10 years of quitting, ex-smokers avoided an estimated 64% of cardiovascular mortality, 53% of cancer mortality, and 57% of respiratory mortality associated with current smoking, said the research letter, “Association of Smoking Cessation and Cardiovascular, Cancer, and Respiratory Mortality,” published in JAMA Internal Medicine. More time off tobacco led to more health benefits. “After 30 or more years of smoking cessation … former smokers avoided an estimated 100%, 93%, and 97% of the excess cardiovascular, cancer, and respiratory mortality associated with continued smoking, respectively,” the study said. Once smokers stop, the researchers noted there is conflicting evidence about whether increased risk to heart health decreases over 10 to 20 years, or decades later. Cardiovascular disease risk may remain elevated approximately 20 years after quitting, according to previous studies. Even so, “the hazards of smoking and benefits of quitting may be underestimated,” and over time, ex-smokers may have started again, while some current smokers quit, the study said. “These findings emphasize that with sustained cessation, cause-specific mortality rates among former smokers may eventually approximate those of never smokers,” the study said. The data came from the National Health Interview Survey from 1997 followed up through the end of 2019, via linkage to the National Death Index.