Minimizing Venous Thromboembolism in Feminizing Hormone Therapy: Applying Lessons From Cisgender Women and Previous Data

ObjectiveTo review he impact of estrogen-containing feminizing hormone regimens on transgender individuals’ risk for VTE.MethodsWe evaluated VTE risk by screening 1170 relevant studies published from 1994 to 2020, focusing on meta-analysis data.ResultsThe type of oral estrogen, route of administration, patient demographics, and comorbidities may affect the risk of VTE. Venous thrombosis is the most common vascular complication associated with HT.ConclusionConjugated equine estrogens and 17-β estradiol appear to be safer than oral ethinyl estradiol. Transdermal estrogen formulations appear to be the least thrombogenic estrogens. Estrogens used concomitantly with progestins increase the risk of VTE compared to estrogens alone.To date, there are no data to demonstrate the benefit of holding HT prior to vaginoplasty or other gender affirming surgeries. For most young, healthy transgender women, there is little risk of VTE with HT, while older patients with risk factors should be discussed case by case.     

Assessing and Addressing the Risk of Venous Thromboembolism Across the Spectrum of Gender Affirming Care: A Review

ObjectiveAccumulating evidence demonstrates that gender affirming hormone therapy (GAHT) improves mental health outcomes in transgender persons. Data specific to the risks associated with GAHT for transgender persons continue to emerge, allowing for improvements in understanding, predicting, and mitigating adverse outcomes while informing discussion about desired effects. Of particular concern is the risk of venous thromboembolism (VTE) in the context of both longitudinal GAHT and the perioperative setting. Combining what is known about the risk of VTE in cisgender individuals on hormone therapy (HT) with the evidence for transgender persons receiving HT allows for an informed approach to assess underlying risk and improve care in the transgender community.ObservationsHormone formulation, dosing, route, and duration of therapy can impact thromboembolic risk, with transdermal estrogen formulations having the lowest risk. There are no existing risk scores for VTE that consider HT as a possible risk factor. Risk assessment for recurrent VTE and bleeding tendencies using current scores may be helpful when assessing individual risk. Gender affirming surgeries present unique perioperative concerns, and certain procedures include a high likelihood that patients will be on exogenous estrogens at the time of surgery, potentially increasing thromboembolic risk.Conclusions and RelevanceWithholding GAHT due to potential adverse events may cause negative impacts for individual patients. Providers should be knowledgeable about the management of HT in transgender individuals of all ages, as well as in the perioperative setting, to avoid periods in which transgender individuals are off GAHT. Treatment decisions for both anticoagulation and HT should be individualized and tailored to patients’ overall goals and desired outcomes, given that the physical and mental health benefits of gender affirming care may outweigh the risk of VTE.     

The Effect of Gender-Affirming Hormone Therapy on the Risk of Subclinical Atherosclerosis in the Transgender Population: A Systematic Review

ObjectiveThe impact of gender-affirming hormone therapy (GAHT) on cardiovascular (CV) health is still not entirely established. A systematic review was conducted to summarize the evidence on the risk of subclinical atherosclerosis in transgender people receiving GAHT.MethodsA systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, and data were searched in PubMed, LILACS, EMBASE, and Scopus databases for cohort, case-control, and cross-sectional studies or randomized clinical trials, including transgender people receiving GAHT. Transgender men and women before and during/after GAHT for at least 2 months, compared with cisgender men and women or hormonally untreated transgender persons. Studies reporting changes in variables related to endothelial function, arterial stiffness, autonomic function, and blood markers of inflammation/coagulation associated with CV risk were included.ResultsFrom 159 potentially eligible studies initially identified, 12 were included in the systematic review (8 cross-sectional and 4 cohort studies). Studies of trans men receiving GAHT reported increased carotid thickness, brachial-ankle pulse wave velocity, and decreased vasodilation. Studies of trans women receiving GAHT reported decreased interleukin 6, plasminogen activator inhibitor-1, and tissue plasminogen activator levels and brachial-ankle pulse wave velocity, with variations in flow-mediated dilation and arterial stiffness depending on the type of treatment and route of administration.ConclusionsThe results suggest that GAHT is associated with an increased risk of subclinical atherosclerosis in transgender men but may have either neutral or beneficial effects in transgender women. The evidence produced is not entirely conclusive, suggesting that additional studies are warranted in the context of primary prevention of CV disease in the transgender population receiving GAHT.Systematic Review RegistrationPROSPERO, identifier CRD42022323757.     

Cardiovascular Disease in Women Update: Ischemia,Diagnostic Testing,and Menopause Hormone Therapy

ObjectiveThis update will address 3 areas specifically that are essential to improving cardiovascular outcomes for women.MethodsThe current literature has been reviewed and three important areas of cardiovascular care in women are highlighted. First is that even though women and men share many traditional risk factors for ischemic heart disease, several of these risk factors affect women disproportionately when it comes to CVD risk and events. There are also unique sex-specific risk factors for women and risk factors that are more common in women than in men. Adverse outcomes of pregnancy and hypertensive disorders of pregnancy are associated with an increased long-term risk of CVD and events. At menopause, cardiovascular risks increase, and lipids become unfavorable. Second is that diagnostic testing for ischemic heart disease presents different specificities and sensitivities between men and women and testing should be determined according to what is best and safest for women. Third is that currently, menopause hormone therapy is approved by the U.S. Food and Drug Administration for the treatment of vasomotor and genitourinary symptoms, prevention of osteoporosis, and estrogen replacement in the setting of surgical menopause, hypogonadism, or premature ovarian insufficiency. It is not recommended for the primary or secondary prevention of CVD and not recommended for women with high atherosclerotic CVD risk.ResultsCardiovascular disease (CVD) remains the most common cause of death in women in the United States despite tremendous improvements in cardiovascular care for men and women. The prevention of CVD in women with early detection and implementation of preventive therapies before atherosclerotic CVD develops is critical to improving outcomes for women.     

Risk Assessment and Coronary Artery Calcium Scoring in Transgender and Gender-Diverse Individuals Receiving Gender-Affirming Hormone Therapy

ObjectiveTo evaluate cardiovascular risk factors and prevalent coronary artery disease (CAD) using Coronary Artery Calcium (CAC) scoring in transgender and gender-diverse (TGD) individuals receiving gender-affirming hormone therapy (GAHT) and compare the CAC scores of TGD individuals with those of the general population.MethodsTGD individuals aged ≥30 years, without known risk factors for cardiovascular disease (CVD), other than tobacco use and family history of CVD, on GAHT were recruited, and baseline information, including metabolic parameters, was collected. CAC scores were obtained and compared with those of a cisgender age-matched population.ResultsOf 25 transwomen recruited, 24 underwent CAC scans. Of them, 2 (8.3%) had a CAC score of >0 to 99 and 1 (4.1%) had a CAC score of ≥100. Of 22 transmen recruited, 16 underwent CAC scans. Of them, 26 (12.5%) had a CAC score of >0 to 99 and none had a CAC score of ≥100. Framingham Risk Scores were not correlated with the presence of CAC.ConclusionThe presence of CAC in this small cohort of TGD individuals on GAHT was similar to that in the cisgender age-matched population. CAC scoring is a means to assess the prevalence of CAD in TGD individuals and identify those in whom aggressive risk reduction is indicated.     

Racial and Ethnic Cardiometabolic Risk Disparities in the Type 1 Diabetes Exchange Clinic Registry Cohort

ObjectiveTo determine whether individuals from a historically underrepresented racial group have a higher cardiometabolic risk than historically represented individuals with type 1 diabetes (T1D) considering socioeconomic deprivation.MethodsWe used the multivariable logistic and linear regression models to examine socioeconomic deprivation (upper 10th percentile) by race/ethnicity interaction for each cardiometabolic risk factor and cardiometabolic risk burden score, respectively, across 6320 zip code tabulation areas. We also determined the age-adjusted prevalence of low, moderate, and high cardiometabolic risks defined as 0, 1 to 2, and 3 or more risk factors for hypertension, obesity, dyslipidemia, and off-target glycemia for non-Hispanic White (n = 15 746), non-Hispanic Black (n = 1019), Hispanic (n = 1115), and other (n = 887), respectively.ResultsThe sample comprised 18 767 adolescents and adults with T1D. Those identifying as non-Hispanic Black were more likely to have a high cardiometabolic risk profile, including a 4.5-fold increase in the odds of off-target glycemia, a twofold increase in the odds of systolic hypertension, and 0.29 (unadjusted) and 0.46 (adjusted) increases in a higher cardiometabolic risk burden compared with non-Hispanic White individuals (P < .01). Those identifying as Hispanic had a 3.4-fold increase in the odds of off-target glycemia but were less likely to be overweight/obese or have systolic hypertension compared with non-Hispanic White. However, the lower likelihood of overweight/obesity and hypertension did not persist after considering covariates.ConclusionThere is a need to investigate additional determinants of racially/ethnically underrepresented cardiometabolic health, including structural racism and implicit bias in cardiometabolic care for individuals with T1D.     

Metabolic Associated Fatty Liver Disease Increases the Risk of Systemic Complications and Mortality. A Meta-Analysis and Systematic Review of 12 620 736 Individuals

ObjectiveThe recent introduction of the term metabolic associated fatty liver disease (MAFLD) sought to reclassify nonalcoholic fatty liver disease (NAFLD). MAFLD is thought to improve the encapsulation of metabolic dysregulation. However, recent evidence has found significant differences between MAFLD and NAFLD, and prevailing knowledge has largely arisen from studies on NAFLD. Hence, we conducted a meta-analysis and systematic review of the outcomes associated with MAFLD.MethodsMEDLINE and Embase databases were searched for articles relating to outcomes in MAFLD. Analysis was conducted in random effects with hazard ratios (HRs) to account for longitudinal risk assessment of mortality and systemic complications.ResultsA total of 554 articles were identified, of which 17 articles were included. MAFLD resulted in an increase in the overall mortality (HR, 1.24; confidence interval [CI], 1.13-1.34), cancer-related mortality (HR, 1.27; CI, 1.01-1.54), and cardiovascular disease mortality (HR, 1.28, 1.03-1.53; P = .04) compared with non-MAFLD. MAFLD also increases the risk of cardiovascular events (HR, 1.49; CI, 1.34-1.64; P < .01), stroke (HR, 1.55; CI, 1.37-1.73; P < .01), and chronic kidney disease (HR, 1.53; CI, 1.38-1.68). The presence of MAFLD was also associated with an increased risk of heart failure, obstructive sleep apnea, and malignancy.ConclusionMAFLD can significantly elevate the risk of systemic diseases and mortality. The care of MAFLD thus requires interdisciplinary collaboration, and future clinical trials conducted on MAFLD should aim to reduce the incidence of end-organ damage aside from improving liver histology.     

Management of Mild-to-Moderate Hypertriglyceridemia

ObjectiveHypertriglyceridemia (HTG) is highly prevalent globally, and its prevalence is rising, with a worldwide increase in the incidence of obesity and diabetes. This review examines its current management and future therapies.MethodsFor this review, HTG is defined as mild-to-moderate elevation in the levels of triglyceride (TG): a fasting or nonfasting TG level of ≥150 mg/dL and <500 mg/dL. We reviewed scientific studies published over the last 30 years and current professional society recommendations regarding the evaluation and treatment of HTG.ResultsGenetics, lifestyle, and other environmental factors impact TG levels. In adults with mild-to-moderate HTG, clinicians should routinely assess and treat secondary treatable causes (diet, physical activity, obesity, metabolic syndrome, and reduction or cessation of medications that elevate TG levels). Because atherosclerotic cardiovascular disease risk is the primary clinical concern, statins are usually the first-line treatment. Patients with TG levels between ≥150 mg/dL and <500 mg/dL whose low-density lipoprotein cholesterol is treated adequately with statins (at “maximally tolerated“ doses, per some statements) and have either prior cardiovascular disease or diabetes mellitus along with at least 2 additional cardiovascular disease risk factors should be considered for added icosapent ethyl treatment to further reduce their cardiovascular disease risk. Fibrates, niacin, and other approved agents or agents under development are also reviewed in detail.ConclusionThe treatment paradigm for mild-to-moderate HTG is changing on the basis of data from recent clinical trials. Recent trials suggest that the addition of icosapent ethyl to background statin therapy may further reduce atherosclerotic cardiovascular disease risk in patients with moderate HTG, although a particular TG goal has not been identified.     

Statin Intolerance: A Review and Update

ObjectiveTo review the evidence of existing literature on the management of statin intolerance.MethodsWe searched for literature pertaining to statin intolerance and treatments in PubMed. We reviewed articles published between 2005 and 2022.ResultsStatin-associated myalgia is the most common adverse effect of statin therapy and the most common reason for statin discontinuation. The risk factors for statin intolerance include unexplained muscle pain with other lipid-lowering therapy, unexplained cramps, a history of increased creatine kinase levels, a family history of muscle symptoms, and a family history of muscle symptoms with lipid therapy. Vitamin D repletion and coenzyme Q supplementation may help alleviate the musculoskeletal effects of statins. Trials of different types of statins and different dosing regimens are recommended to improve tolerability. The use of statins in individuals who perform regular exercise requires closer attention to muscular symptoms and creatine kinase levels; however, it does not preclude the use of statins.ConclusionManagement of the adverse effects of statin therapy and improving statin tolerability are key to achieving optimum cardiovascular benefits. Identifying statin-associated adverse effects and managing them appropriately can reduce unnecessary statin discontinuation and subsequently provide longer cardiovascular protection.     

Age-Related Factors Associated With The Risk of Hip Fracture

ObjectiveAdvancing age is a powerful risk factor for hip fractures. The biological mechanisms through which aging impacts the risk of hip fractures have not been well studied.MethodsBiological factors associated with “advancing age” that help to explain how aging is associated with the risk of hip fractures are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults aged ≥65 years with 25 years of follow-up.ResultsThe following 5 age-related factors were found to be significantly associated with the risk of hip fractures: (1) microvascular disease of the kidneys (albuminuria and/or elevated urine-albumin-to-creatinine ratio) and brain (abnormal white matter disease on brain magnetic resonance imaging); (2) increased serum levels of carboxymethyl-lysine, an advanced glycation end product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased transfatty acid levels in the blood. Each of these factors was associated with a 10% to 25% increased risk of fractures. These associations were independent of traditional risk factors for hip fractures.ConclusionSeveral factors associated with older age help to explain how “aging” may be associated with the risk of hip fractures. These same factors may also explain the high risk of mortality following hip fractures.     

Ideal Cardiovascular Health and Adipokine Levels: The Multi-Ethnic Study of Atherosclerosis

ObjectiveTo evaluate the association between ideal cardiovascular health (CVH) and adipokine levels. Adipokines are hormones implicated in obesity and its cardiometabolic consequences. The concept of ideal CVH was introduced to promote 7 key health factors and behaviors in the general population. Previous studies have found strong associations between obesity and ideal CVH. However, existing literature on the link between CVH and adipokines is scarce.MethodsWe studied 1842 Multi-Ethnic Study of Atherosclerosis participants free of cardiovascular disease who had 7 CVH metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting blood glucose) measured at baseline and serum adipokine levels measured at a median of 2.4 years later. Each CVH metric was assigned a score of 0 (poor), 1 (intermediate), or 2 (ideal), and all scores were summed for a total CVH score (0-14). The total CVH scores of 0 to 8, 9 to 10, and 11 to 14 were considered inadequate, average, and optimal, respectively. We used multivariable linear regression models to assess the nonconcurrent associations between the CVH score and log-transformed adipokine levels.ResultsThe mean age was 62.1 ± 9.8 years; 50.2% of participants were men. After adjusting for sociodemographic factors, a 1-unit higher CVH score was significantly associated with 4% higher adiponectin and 15% and 1% lower leptin and resistin levels. Individuals with optimal CVH scores had 27% higher adiponectin and 56% lower leptin levels than those with inadequate CVH scores. Similar trends were observed for those with average versus inadequate CVH scores.ConclusionIn a multi-ethnic cohort free of cardiovascular disease at baseline, individuals with average and optimal CVH scores had a more favorable adipokine profile than those with inadequate CVH scores.     

The Effect of Gender-Affirming Hormone Therapy on Serum Creatinine in Transgender Individuals

ObjectiveTo describe the changes in serum creatinine (Cr) levels after the initiation of gender-affirming hormone therapy (GAHT) in transgender individuals to better understand the expected changes and interpretation of laboratory values in this population.MethodsA retrospective chart review of all adult transgender patients initiated on GAHT at Mayo Clinic from January 2011 to October 2019 was completed. Laboratory values were obtained prior to initiating GAHT and at 3, 6, and 12 months after initiating GAHT. Baseline Cr values were compared with Cr values at 3, 6, and 12 months after initiating GAHT in transgender men (TM) on testosterone and transgender women (TW) on estradiol and antiandrogens.ResultsA total of 84 TW (median age of 30 years) and 24 TM (median age of 23 years) were included for analysis. Following a matched pair analysis of TW, Cr values were found to be significantly decreased by ?0.03 at 3 months (P = .04), ?0.10 at 6 months (P < .01), and ?0.07 at 12 months (P < .01) compared with baseline values. Following a matched pair analysis of TM, Cr values were found to be significantly increased, on average, by 0.14 at 3 months (P = .04), 0.21 at 6 months (P = .016), and 0.15 at 12 months (P = .003) compared with baseline values.ConclusionIn TW and TM, a change in Cr level was seen as early as 3 months toward their affirmed gender after initiating GAHT. Clinicians can use Cr levels established at 6 months as new baseline values, as these changes continue to persist up to 12 months.     

Serum Hormone Concentrations in Transgender Individuals Receiving Gender-Affirming Hormone Therapy: A Longitudinal Retrospective Cohort Study

ObjectiveTo examine the association of various gender-affirming hormone therapy regimens with blood sex hormone concentrations in transgender individuals.MethodsThis retrospective study included transgender people receiving gender-affirming hormone therapy between January 2000 and September 2018. Data on patient demographics, laboratory values, and hormone dose and frequency were collected. Nonparametric tests and linear regression analyses were used to identify factors associated with serum hormone concentrations.ResultsOverall, 196 subjects (134 transgender women and 62 transgender men), with a total of 941 clinical visits, were included in this study. Transgender men receiving transdermal testosterone had a significantly lower median concentration of serum total testosterone when compared with those receiving injectable preparations (326.0 ng/dL vs 524.5 ng/dL, respectively, P = .018). Serum total estradiol concentrations in the transgender women were higher in those receiving intramuscular estrogen compared with those receiving oral and transdermal estrogen (366.0 pg/mL vs 102.0 pg/mL vs 70.8 pg/mL, respectively, P < .001). A dose-dependent increase in the hormone levels was observed for oral estradiol (P < .001) and injectable testosterone (P = .018) but not for intramuscular and transdermal estradiol. Older age and a history of gonadectomy in both the transgender men and women were associated with significantly higher concentrations of serum gender-affirming sex hormones.ConclusionIn the transgender men, all routes and formulations of testosterone appeared to be equally effective in achieving concentrations in the male range. The intramuscular injections of estradiol resulted in the highest serum concentrations of estradiol, whereas transdermal estradiol resulted in the lowest concentration. There was positive relationship between both oral estradiol and injectable testosterone dose and serum sex hormone concentrations in transgender people receiving GAHT.     

The Prevalence of Dysglycemia-Based Chronic Disease in a European Population – a New Paradigm to Address Diabetes Burden: A Kardiovize Study

ObjectiveTo determine the prevalence rate and associated risk factors for each stage of the Dysglycemia-Based Chronic Disease (DBCD) model, which 4 distinct stages and prompts early prevention to avert Diabetes and cardiometabolic complications.MethodsSubjects between 25 and 64 years old from a random population-based sample were evaluated in Czechia from 2013 to 2014 using a cross-sectional design. DBCD stages were: stage 1 “insulin resistance” (inferred risk from abdominal obesity or a family history of diabetes); stage 2 “prediabetes”(fasting glucose between 5.6 and 6.9 mmol/L); stage 3 “type 2 diabetes (T2D)” (self-report of T2D or fasting glucose ≥7 mmol/L); and stage 4 “vascular complications” (T2D with cardiovascular disease).ResultsA total of 2147 subjects were included (57.8% women) with a median age of 48 years. The prevalence of each DBCD stage were as follows: 54.2% (stage 1); 10.3% (stage 2), 3.7% (stage 3); and 1.2% (stage 4). Stages 2 to 4 were more frequent in men and stage 1 in women (P < .001). Using binary logistic regression analysis adjusting by age/sex, all DBCD stages were strongly associated with abnormal adiposity, hypertension, dyslipidemia, and smoking status. Subjects with lower educational levels and lower income were more likely to present DBCD.ConclusionUsing the new DBCD framework and available metrics, 69.4% of the population had DBCD, identifying far more people at risk than a simple prevalence rate for T2D (9.2% in Czechia, 2013-2014). All stages were associated with traditional cardiometabolic risk factors, implicating common pathophysiologic mechanisms and a potential for early preventive care. The social determinants of health were related with all DBCD stages in alarming proportions and will need to be further studied.     

Comparison of the Subcutaneous and Intramuscular Estradiol Regimens as Part of Gender-Affirming Hormone Therapy

ObjectiveGender-affirming hormone therapy guidelines describe the estradiol (E2) doses for intramuscular (IM), but not subcutaneous (SC), routes. The objective was to compare the SC and IM E2 doses and hormone levels in transgender and gender diverse individuals.MethodsThis is a retrospective cohort study at a single-site tertiary care referral center. Patients were transgender and gender diverse individuals who received injectable E2 with at least 2 E2 measurements. The main outcomes were the dose and serum hormone levels between the SC and IM routes.ResultsThere were no statistically significant differences in age, body mass index, or antiandrogen use between patients on SC (n = 74) and those on IM (n = 56). The weekly doses of SC E2, 3.75 mg (IQR, 3-4 mg), were statistically significantly lower than those of IM E2, 4 mg (IQR, 3-5.15 mg) (P =.005); however, the E2 levels achieved were not significantly different (P =.69), and the testosterone levels were in the cisgender female range and not significantly different between routes (P =.92). Subgroup analysis demonstrated significantly higher doses in the IM group when the E2 and testosterone levels were >100 pg/mL and <50 ng/dL, respectively, with the presence of the gonads or use of antiandrogens. Multiple regression analysis demonstrated that the dose was significantly associated with the E2 levels after adjusting for injection route, body mass index, antiandrogen use, and gonadectomy status.ConclusionBoth the SC and IM E2 achieve therapeutic E2 levels without a significant difference in the dose (3.75 vs 4 mg). SC may achieve therapeutic levels at lower doses than IM .     

Predictors of Severe COVID-19 in Patients With Diabetes: A Multicenter Review

ObjectiveDiabetes is an independent risk factor for severe SARS-CoV-2 infections. This study aims to elucidate the risk factors predictive of more severe outcomes in patients with diabetes by comparing the clinical characteristics of those requiring inpatient admissions with those who remain outpatient.MethodsA retrospective review identified 832 patients—631 inpatients and 201 outpatients—with diabetes and a positive SARS-CoV-2 test result between March 1 and June 15, 2020. Comparisons between the outpatient and inpatient cohorts were conducted to identify risk factors associated with severity of disease determined by admission rate and mortality. Previous dipeptidyl peptidase 4 inhibitor use and disease outcomes were analyzed.ResultsRisk factors for increased admission included older age (odds ratio [OR], 1.04 [95% CI, 1.01-1.06]; P = .003), the presence of chronic kidney disease (OR, 2.32 [1.26-4.28]; P = .007), and a higher hemoglobin A1c at the time of admission (OR, 1.25 [1.12-1.39]; P < .001). Lower admission rates were seen in those with commercial insurance. Increased mortality was seen in individuals with older age (OR, 1.09 [1.07-1.11]; P < .001), higher body mass index number (OR, 1.04 [1.01-1.07]; P = .003), and higher hemoglobin A1c value at the time of diagnosis of COVID-19 (OR, 1.12 [1.01-1.24]; P = .028) and patients requiring hospitalization. Lower mortality was seen in those with hyperlipidemia. Dipeptidyl peptidase 4 inhibitor use prior to COVID-19 infection was not associated with a decreased hospitalization rate.ConclusionThis retrospective review offers the first analysis of outpatient predictors for admission rate and mortality of COVID-19 in patients with diabetes.     

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease,the Impact of Available Lipid-Lowering Medications on Lipoprotein(a): An Update on New Therapies

ObjectiveTo review evidence of existing and new pharmacological therapies for lowering lipoprotein(a) (Lp[a]) concentrations and their impact on clinically relevant outcomes.MethodsWe searched for literature pertaining to Lp(a) and pharmacological treatments in PubMed. We reviewed articles published between 1963 and 2020.ResultsWe found that statins significantly increased Lp(a) concentrations. Therapies that demonstrated varying degrees of Lp(a) reduction included ezetimibe, niacin, proprotein convertase subtilisin/kexin type 9 inhibitors, lipoprotein apheresis, fibrates, aspirin, hormone replacement therapy, antisense oligonucleotide therapy, and small interfering RNA therapy. There was limited data from large observational studies and post hoc analyses showing the potential benefits of these therapies in improving cardiovascular outcomes.ConclusionThere are multiple lipid-lowering agents currently being used to treat hyperlipidemia that also have a Lp(a)-lowering effect. Two RNA therapies specifically targeted to lower Lp(a) are being investigated in phase 3 clinical trials and, thus far, have shown promising results. However, evidence is lacking to determine the clinical relevance of reducing Lp(a). At present, there is a need for large-scale, randomized, controlled trials to evaluate cardiovascular outcomes associated with lowering Lp(a).     

COUNTERPOINT: Artificial Sweeteners for Obesity—Better than Sugary Alternatives; Potentially a Solution

ObjectiveNonnutritive (NNSs) are used in place of sugars to reduce caloric and glycemic intake while providing desired sweetness, commonly replacing sugar-sweetened beverages (SSBs) with “diet” (zero-calorie) alternatives. Concern has developed due to observational data associating NNSs with obesity and adiposity-based chronic disease. This counterpoint argues that, in general, NNSs used in place of added or excess sugars in the diet are likely beneficial.MethodsA literature review was conducted on interventional trials investigating NNSs and obesity or type 2 diabetes mellitus. Key words used in the search included artificial sweeteners, nonnutritive sweeteners, saccharin, sucralose, aspartame, stevia/steviol, acesulfame potassium, meal replacements, type 2 diabetes mellitus, obesity, and weight.ResultsInterventional data and indirect interventional data consistently showed beneficial effects on weight and cardiometabolic health, including glycemia, when SSBs or other energy-dense foods were replaced by artificially sweetened beverages or artificially sweetened meal replacements.ConclusionAlthough NNSs correlate with obesity and adiposity-based chronic disease, those data are fraught with confounding and error. Plausibility has been suggested on the basis of preclinical research on neuroendocrine control of appetite, satiety, and cravings plus the gut microbiome. However, interventional data reveal that replacing caloric/glycemic energy intake via NNSs creates an energy deficit resulting in weight loss and improvement in disease—especially dysglycemic disease. Intensive dietary intervention using artificially sweetened meal replacements shows a marked clinical benefit without detriment from their NNSs. Furthermore, beverages sweetened with NNSs rather than SSBs have been noted to be a critical component for those succeeding in maintaining weight loss. Although individual responses to the effects of NNSs are always warranted just like in any clinical situation, patients should not be advised to avoid NNSs in the context of dietary intervention to improve quality and energy deficit.     

Denosumab Use in Adults With Fibrous Dysplasia: Case Reports and Review of the Literature

ObjectiveIn fibrous dysplasia (FD) of the bone, a gain-of-function mutation in the G-nucleotide binding protein alpha subunit results in constitutively active cyclic adenosine monophosphate. Downstream effects include formation of disorganized cortex and bone marrow fibrosis. Patients with FD experience bone pain and are at risk of fracture. Bisphosphonates are traditionally used to manage pain with mixed results. We sought to report denosumab use in patients with FD at our institution and summarized the existing literature on denosumab use in FD.MethodsWe retrospectively identified patients with FD who were treated with denosumab at our institution, describing patient characteristics and outcomes. We reviewed the existing literature on denosumab use in patients with FD.ResultsPatient 1 was diagnosed with FD at the age of 17 years and took bisphosphonates with initial improvement in pain. Pain eventually worsened; therefore, she received 4 doses of denosumab. Patient 2 was diagnosed with FD after a fall and was treated with bisphosphonates, reporting some initial improvement in bone pain. A few years later, the pain recurred, and he received 3 doses of denosumab. Both patients tolerated denosumab well but experienced no improvement in pain. On literature review, although some serious side effects were noted, patients experienced a decline in bone turnover markers, and most reported improvement in bone pain with denosumab.ConclusionDenosumab is a promising therapy for managing symptoms of FD. Further studies are needed to determine the optimal dose and duration of treatment. Its long-term effect on FD lesions remains unclear.