Marketing and Testosterone Treatment in the USA: A Systematic Review.

CONTEXT: Testosterone replacement therapy (TRT) is currently approved by the Food and Drug Administration only for classic hypogonadism, although off-label indications have resulted in a dramatic expansion in prescriptions in the USA. Marketing may significantly affect prescriber behavior. OBJECTIVE: To systematically review all available evidence on marketing and TRT in the USA. EVIDENCE ACQUISITION: PubMed, Embase, and Scopus were searched up to July 2017 for all relevant publications reporting on assessments of the TRT market size, economic costs associated with hypogonadism, trends in TRT prescriptions, drug discontinuation rates, and advertising and sales efforts in the USA. EVIDENCE SYNTHESIS: Twenty retrospective studies were included in the final analysis. The market size for hypogonadism constitutes 5.6-76.8% of men in the USA, with the lower end of the range representing the strictest criteria for diagnosis. Men with a diagnosis of hypogonadism consume $14 118 in direct and indirect costs to the payer. Over the last 2 decades, TRT prescriptions have increased between 1.8- and 4-fold. After 1 yr, 80-85% of men discontinue TRT. There is an association between direct-to-consumer advertising and testosterone testing, TRT prescriptions, and TRT without testosterone testing. There is a high prevalence of misinformation on Internet advertising. CONCLUSIONS: Off-label indications have driven the dramatic expansion of TRT prescriptions over the last 2 decades. Direct-to-consumer advertising poses a unique challenge in the USA. Overtreatment can be avoided by applying strict diagnostic criteria for hypogonadism, which limits the addressable market for TRT. PATIENT SUMMARY: In this report, we reviewed the relationship between marketing and testosterone therapy in the USA. We found that many patients are prescribed testosterone without an appropriate diagnosis of hypogonadism, which may be related to the marketing efforts for off-label prescribing.

Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17α-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost. OBJECTIVE: To examine the hidden cost of anabolic androgen use related to the risk of developing non-HAE comorbidities. METHODS: Patients with HAE were identified in the Southern California Kaiser Permanente database using clinical and laboratory findings compatible with HAE. These patients were stratified into anabolic androgen exposed and nonexposed groups. Matched controls were selected from the Kaiser database who did not have HAE or anabolic androgen exposure. Using multivariate analysis, we determined the number of non-HAE comorbidities linked to anabolic androgen use. We next determined the association between dosing and increasing exposure to anabolic androgens and the likelihood of having various comorbidities. RESULTS: Patients with HAE exposed to anabolic androgens had a 28% increase (P = .04) in non-HAE comorbidities when compared with their matched (nonexposed) controls. With each gram per month increase in exposure, a 12% increase in non-HAE comorbidities is observed (P < .01). The most commonly occurring non-HAE comorbidities were psychiatric, muscle cramps, obesity, and hyperlipidemia. CONCLUSION: Our data suggest that long-term anabolic androgen use enhances the risk of developing comorbid health conditions, thus amplifying the cost of care. Our report provides additional support for the preferred use of newer, targeted therapies for the management of HAE.

The direct and indirect costs among U.S. privately insured employees with hypogonadism.

INTRODUCTION: While previous studies have noted that hypogonadism (HG) may pose a significant economic and quality-of-life burden, no studies have evaluated the impact of HG on healthcare utilization and costs in the United States. AIM: Compare direct (health care) and indirect (disability leave or medical absence) costs between privately insured U.S. employees with HG and controls without HG. METHODS: The study sample included 4,269 male employees, ages 35-64, with ≥ 2 HG diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification: 257.2x) or ≥ 1 HG diagnosis and ≥ 1 claim for testosterone therapy, 1/1/2005-3/31/2009, identified from a large, private insurance administrative database that includes medical, prescription drug, and disability claims data. The index date was the most recent HG diagnosis that had continuous eligibility for at least 1 year before (baseline period) and 1 year after (study period). Employees with HG were matched 1:1 on age, region, salaried vs. nonsalaried employment status, and index year to controls without HG. MAIN OUTCOME MEASURES: Descriptive analyses compared demographic characteristics, comorbidities, resource utilization, direct and indirect costs inflated to USD 2009. Multivariate analyses adjusting for baseline characteristics were used to estimate risk-adjusted costs. RESULTS: HG employees and controls had a mean age of 51 years. HG employees compared with controls had higher baseline comorbidity rates, including hyperlipidemia (50.2% vs. 25.3%), hypertension (37.7% vs. 21.1%), back/neck pain (32.0% vs. 15.7%), and human immunodeficiency virus/acquired immunodeficiency syndrome (7.1% vs. 0.3%) (all P < 0.0001). HG employees had higher mean study period direct ($10,914 vs. $3,823) and indirect costs ($3,204 vs. $1,450); HG-related direct costs were $832 (all P < 0.0001). Risk-adjusted direct ($9,291 vs. $5,248) and indirect ($2,729 vs. $1,840) costs were also higher for HG employees (all P < 0.0001). CONCLUSIONS: Employees with HG had higher comorbidity rates and costs compared with controls. Given the low HG-related costs, a primary driver of costs among HG patients appears to be their comorbidity burden.

Pharmacoepidemiology of testosterone prescribing in Australia, 1992-2010.

OBJECTIVE: To describe patterns of testosterone prescribing in Australia over the past two decades by state or territory and by product type. DESIGN AND SETTING: Observational analysis of testosterone prescribing data obtained from two independent data sources--the Pharmaceutical Benefits Scheme (PBS) and IMS, a source of commercial pharmaceutical sales data. MAIN OUTCOME MEASURES: Temporal trends in testosterone prescribing--measured as units prescribed (converted into monthly defined doses) and expenditure--to state or territory and product type (injectable, implantable, transdermal and oral). RESULTS: Over two decades, total annual expenditure on testosterone products increased ninefold to $12.7 million according to PBS data and fivefold to $16.3 million according to IMS data. When adjusted for inflation and population growth, expenditure increased 4.5-fold according to PBS data and 2.5-fold according to IMS data. The patterns of testosterone prescribing according to PBS and IMS data were highly congruent. When converted into monthly defined dose units, testosterone prescribing increased over the two decades with approximately twofold differences in total testosterone prescribed per capita between the states and territories with the highest and lowest rates of prescribing. When analysed by product type, the stable market patterns over the first 15 years were disrupted by sharp changes to create market dominance owing to introduction of two new testosterone products--a depot injectable testosterone and a transdermal testosterone gel. CONCLUSIONS: The progressive increase in PBS-subsidised testosterone prescribing without changes in proven medical indications or improvements in diagnosis of pathologically based androgen deficiency are likely to be due to promotion-driven non-compliance with PBS prescribing criteria, indicating that more effective implementation of the criteria is needed.

Determination of PDE-5 inhibitors and appetite suppressants in adulterated dietary supplements using LC/PDA and LC/MS.

There have been a number of reports of dietary supplements contaminated with illegal adulterants that threaten consumers' health because of their adverse pharmacological effects. In the present study, a convenient and economic method was developed to detect illegal pharmaceutics, such as PDE-5 inhibitor and appetite suppressants, using liquid chromatography (LC)/photodiode array (PDA) for screening and LC/mass spectrometry (MS) for successive confirmation. Target peaks were identified by comparison of their chromatographic retention times and PDA spectra with those of synthetic standards and finally confirmed by LC/MS. As a result, tadalafil, a PDE-5 inhibitor, and N-desmethylsibutramine, a derivative of sibutramine, were detected in various dietary supplements at concentrations of 13.5-21.9 mg and 3.0 mg per single dose, respectively. The present study will contribute to the development of an analytical method enabling rapid screening of a variety of health foods, and the result suggests that consumers should be aware of serious health risks related to these illegal compounds.

Selling androgenic anabolic steroids by the pound: identification and analysis of popular websites on the Internet.

Internet websites offering androgenic anabolic steroids (AAS) were identified and available products were examined. Keywords for the website search were: "anabolic steroids," "anabolic steroids buy," "anabolic steroid purchase." The first 10 websites offering AAS in the first 10 pages of results were considered. At least two AAS-containing products per website were selected. Thirty AAS-selling websites were identified, mainly located in the United States (46.7%) and Europe (30%). Most websites sold other anabolic/ergogenic products (clenbuterol, 76.7%; GH/IGF, 60.0%; thyroid hormones, 46.7%; erythropoietin, 30.0%; insulin, 20.0%) or products for AAS-related adverse effects (mainly: estrogen antagonists, 63.3%; products for erectile dysfunction, 56.7%; 5α-reductase inhibitors, 33.3%; anti-acne products, 33.3%). AAS were sold as medicines (69.6%) or as dietary supplements (30.4%). AAS in medicines were mainly: nandronole (20.4%), methandrostenolone (18.4%), and testosterone (12.2%). Dietary supplements contained mainly DHEA and included several fake compounds. Manufacturers were declared for 97.9% of medicines and 66.7% of dietary supplements; however, several manufacturers were not found on the Internet. Described benefits were usually few adverse effects and no estrogenicity. Toxicity was seldom reported and presented as mild. Recommended doses were two-fourfold higher than current medical recommendations. In conclusion, misleading information and deceiving practices were common findings on AAS-selling websites, indicating their deleterious potential for public health.

The burden of testosterone deficiency syndrome in adult men: economic and quality-of-life impact.

INTRODUCTION: Testosterone deficiency syndrome (TDS) causes a wide range of symptoms that can lead to significant morbidity. Preliminary evidence has also linked TDS with premature mortality and with a number of comorbid diseases including diabetes and metabolic syndrome. Such associations can lead to substantial economic and quality-of-life implications, the magnitude of which remains largely unknown. AIM: To review the economic and quality-of-life consequences of a largely untreated condition and to consider the likely health economic benefits of testosterone treatment. METHODS: A systematic review of four main areas: epidemiological evidence of the magnitude of TDS, estimates of cost of illness, impact on quality-of-life, and cost-effectiveness of testosterone treatment. MAIN OUTCOME MEASURE: Review of peer-reviewed literature. RESULTS: The lack of clear universally accepted diagnostic criteria and the uncertainty surrounding the link between TDS and some of its consequences complicate the estimation of the burden of illness of TDS. Consequences of TDS that potentially lead to increased economic burden include depression, sexual dysfunction, mild cognitive impairment, osteoporosis, cardiovascular disease, and mortality. However, although good evidence exists demonstrating an association between TDS and sexual dysfunction and cognitive impairment, evidence is less strong for depression, the incidence of fractures and mortality, and highly controversial for cardiovascular disease. The consequences that are likely to impact on patients' quality of life include sexual function, energy levels, body composition, mood, and cognitive function. CONCLUSION: Understanding the burden is only the first step decision makers need to take to decide whether to allocate scarce resources to treat the condition. To make informed decisions on when and who to treat information is also needed on the cost-effectiveness of available treatments. Such data would highlight the benefits of treatment of TDS to physicians, patients, and to society as a whole.

Pharmacologic adjuvants to epoetin in the treatment of anemia in patients on hemodialysis.

Anemia is a common complication of chronic kidney disease, particularly in patients who are on dialysis. The use of recombinant human erythropoietin has led to the eradication of severe anemia in the dialysis population. Correction of anemia in these patients has been associated with better quality of life and clinical outcomes. Some hemodialysis patients have anemia that either is relatively refractory to epoetin therapy or requires very high doses of epoetin (i.e., hyporesponsiveness), despite having adequate iron stores, and are thus unable to achieve or maintain target hemoglobin levels. Several pharmacologic agents have been studied for effects on improving response to epoetin, either to counter hyporesponsiveness or simply to reduce epoetin use for purely economic reasons. This review examines the available literature regarding the efficacy of these potential pharmacologic adjuvants to epoetin in the treatment of anemia in patients on maintenance hemodialysis, with special emphasis on androgens, vitamin C (ascorbic acid), and L-carnitine. A review of published guidelines and recommendations for use of these agents in hemodialysis patients is provided.

Program savings associated with switching testosterone intramuscular injections to topical gel in HIV infected males.

BACKGROUND: HIV-1 infected male patients commonly require testosterone supplementation and intramuscular testosterone (IM) is the most frequently used supplementation method. Currently, the economic burden of testosterone supplementation is borne to a large degree by the clinic providing services to the HIV infected male. Increasingly, clinics are seeking alternative methods to provide supplementation. This analysis describes the economic trade-offs associated with the utilization of topically applied testosterone supplement relative to current supplementation techniques within the clinic setting. METHODS: Twenty-three patients that had been receiving IM were switched to topical testosterone gel (TOP). A 1-month time-and-motion study, identification of IM administration specific supplies, and costs for acquisition and disposal of these supplies were conducted or gathered to quantify costs of providing bi-weekly IM to patients. The analysis describes potential resource savings by switching 23 HIV patients served in a safety-net provider setting from IM to TOP. The analysis considers both a pre and post-evaluation period whereby patients received IM in the pre-evaluation period and then were switched to TOP in the follow-up period. Economic assessments considered direct medical costs for the preparation and administration of the product but did not incorporate other outcomes in the analyses. RESULTS: Only one of 23 patients switched experienced recurrence of symptoms and no patients developed adverse effects associated with the switch. In contrast, substantial resources could be realized with the utilization of the topically applied testosterone relative to the injectable formulations with approximately $80,938 fewer dollars spent on provision of IM. CONCLUSIONS: Switching patients from IM to TOP resulted in no deleterious affects and is estimated to have saved the clinic considerable resources, even if TOP had to be provided by the clinic.

Cost implications to Medicare of recombinant erythropoietin therapy for the anemia of end-stage renal disease.

The purpose of this study was to estimate the net cost effect to Medicare of the increasing use of recombinant human erythropoietin (EPO) instead of red blood cell transfusions or androgens in the management of anemia for the approximately 100,000 hemodialysis patients in the U.S. End-Stage Renal Disease (ESRD) program. A computerized decision model that takes into account the effectiveness and possible side effects of transfusions, androgens, and EPO and predicts 1- and 5-yr direct medical costs to Medicare associated with each therapy was constructed. Probability estimates for clinical events were derived from the literature. Costs were assigned by use of the amounts Medicare pays providers of ESRD care for: (1) use of EPO, transfusions, and androgens; and (2) health care services related to the treatment of anemia (including complications of treatment and possible reductions in morbidity). For every 10,000 hemodialysis patients treated with EPO, net Medicare expenditures will be much greater than if only transfusions are used by $42,530,000 at 1 yr (6% of ESRD program costs) and by $118,050,000 at 5 yr and also much greater than if androgens are used (by $42,700,000 at 1 yr and $118,370,000 at 5 yr). The increase in cost was highly sensitive to the dose of EPO; moderately sensitive to changes in estimated anemia response rates for EPO, frequency of EPO-induced vascular access clotting, and reduction in cardiovascular or overall morbidity; and slightly sensitive to transfusion rates, estimated anemia response rates for androgens, frequency of EPO-induced seizure or hypertensive complications (stroke, myocardial infarction), frequency of transfusion-related viral infection, and frequency of androgen-induced virilization. Considering both effectiveness and side effects of alternative treatments for the anemia of ESRD, it was projected that the increasing use of EPO will markedly increase the cost to Medicare of ESRD medical care.