Testosterone Replacement Therapy: Trends, Evidence, and Patient Care Plan

1. Clinical Pearls: Testosterone Replacement TherapyArkansas Association of Health-System Pharmacists 2017 Fall Seminar Alicia Sutterfield, MT, PharmD PGY2 Ambulatory Care Pharmacy Resident Central Arkansas Veterans Healthcare System

2. Disclosure • I have no financial or non-financial conflicts of interest to disclose.

3. Pharmacist Objectives • Describe recent trends in prescribing of testosterone replacement therapy. • Appraise the current evidence for the use of testosterone replacement therapy in aging males. • Formulate a patient care plan for testosterone replacement therapy, balancing the risks vs benefits.

4. Technician Objectives • Discuss recent trends in prescribing of testosterone replacement therapy. • Evaluate the current evidence for the use of testosterone replacement therapy in aging males. • Create a patient care plan which balances the risks vs benefitsof testosterone replacement therapy.

5. Testosterone Replacement Therapy Handelsman, 2013

6. 2016 Update on Medical Overuse:A Systematic Review • Overuse of testing • Imaging for low-risk headaches • Hospitalization for low-risk syncope • Too frequent colonoscopy screenings • Overtreatment • Anticoagulation for Afib with a CHADS2 or CHA2DS2-VASc = 0 • Inappropriate testosterone replacement prescribing • Continued prescribing of opioids after over-dose • Intensive glycemic control in older adults • Services to question • Oxycodone/acetaminophen and cyclobenzaprine for acute low back pain • Over-diagnosis of C. diff with molecular testing • Serial follow-up of benign thyroid nodules Morgan et al., 2016

7. Testosterone Marketing “Testosterone is the life source for the male body... …It’s what makes a man a man” “There are countless studies that have shown not only the safety of hormone therapy, but also the long-term health benefits.” ”It is medical science at its best.” https://www.renewyouth.com

8. Male Testosterone Levels An Introduction to Clinical Medicine, McGraw Hill 2013

9. Androgen Deficiency An Introduction to Clinical Medicine, McGraw Hill 2013

10. Endocrine Society Clinical Practice Guidelines for Male Hypogonadism Diagnosis: • Signs and symptoms consistent with androgen deficiency • Low morning levels of total serum testosterone x2 • Luteinizing Hormone • Follicle Stimulating Hormone Bhasin et al., 2010

11. Endocrine Society Clinical Practice Guidelines for Male Hypogonadism Signs and symptoms consistent with androgen deficiency Bhasin et al., 2010

12. Endocrine Society Clinical Practice Guidelines for Male Hypogonadism Testosterone replacement therapy NOT recommended if: • Hx of breast or prostate cancer • High risk for prostate cancer • PSA > 4 ng/ml • PSA > 3 ng/ml + risk factors (race, family history) • Hematocrit > 50% • Severe lower urinary tract symptoms • Untreated severe obstructive sleep apnea • Uncontrolled/poorly controlled heart failure Bhasin et al., 2010

13. Endocrine Society Clinical Practice Guidelines for Male Hypogonadism Bhasin et al., 2010

14. Testosterone Replacement Therapy Linnebur et al., 2009 Chrousos et al., 2009

15. FDA Drug Safety Communication Caution: Use of testosterone products to relieve symptoms in men with low testosterone for no apparent reason other than aging is not an FDA-approved indication. Labeling change required to inform of possible increased risk of heart attack and stroke with use. U.S. Food and Drug Administration, 2015

16. The Testosterone Trials Eligibility Requirements: • Males > 65 years old • Average serum testosterone < 275 ng/dL Intervention: 1% Testosterone Gel (1.25g/pump) 5g daily, titrated to a maximum of 15g daily vs Placebo Gel Snyder et al., 2014

17. * Minimum detectable treatment difference

18. The TOM Trial Testosterone in Older Men with Mobility Limitations Trial • Community dwelling men > 65 years old • Limited mobility • Total testosterone 100-350 ng/dL • 10g testosterone gel (1%) daily vs placebo x6 months Basaria et al., 2013

19. The TOM Trial Testosterone in Older Men with Mobility Limitations Trial • Enrollment terminated • Increased incidence of cardiovascular events in testosterone arm Basaria et al. 2013

20. Systematic Review & Meta-Analysis Association Between TRT and Cardiovascular Events • 27 Randomized Controlled Trials • 2,994 Men • 180 Cardiovascular Events Xu et al., 2013

21. Testosterone Replacement Therapy in Aging Males Summary • Androgen deficiency is a normal process of aging • Evidence does not support a clear benefit for use of TRT in aging males • TRT may be associated with increased risk for cardiovascular events • Not an FDA-approved indication

22. Testosterone Replacement Therapy in Aging Males Recommendations • Judicious selection of candidates for TRT therapy • Pharmacist involvement to improve patient outcomes • Management of comorbidities • Weight loss • Glycemic control • Blood pressure control • Smoking cessation • Avoid alcohol • TRT should not be used to treat side-effects of other medications

23. Patient Case • HgbA1c = 10.3% • Testosterone = 256 ng/dL • Medication List: cyclobenzaprine 10mg PO TID metformin 500mg PO BID metoprolol tartrate 50mg PO BID oxycodone 10mg/APAP 325mg PO q 4-6 hours prn pain simvastatin 20mg PO QHS

24. Patient Case - Question #1 • Mr. LT’s PCP has requested the clinic pharmacist to provide a treatment recommendation. • Testosterone 4mg/hr patch applied once daily QHS • Testosterone 1.62% gel, 2 pumps applied once daily QAM • Testosterone injectable solution, 200mg IM q 2 weeks • None of the above

25. Patient Case - Question #2 • What additional information is recommended prior to initiating TRT? • Repeat testosterone level in 1 week, collected 8-10AM • Luteinizing and follicle-stimulating hormone levels • Baseline hgb/hct, LFT’s, BUN/serum creatinine • Complete medical and family history • All of the above

26. Patient Case - Question #3 • What is the likely etiology for Mr. LT’s symptoms? • Obesity • Poor glycemic control • HTN • Smoking • Chronic opioid use • All of the above

27. Patient Case - Question #4 • What is the best treatment for Mr. LT’s symptoms? • Increase metformin to 1000mg BID and replace metoprolol with HCTZ 25mg QAM • Weight loss to obtain a healthy weight • Smoking cessation • Reduced alcohol consumption • Taper-off opioid therapy • All of the above

28. Questions? • Alicia Sutterfield, MT, PharmD • PGY2 Ambulatory Care Pharmacy Resident • Central Arkansas Veterans Healthcare System • alicia.sutterfield@va.gov

29. References • Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013;199:548-51. doi: 10.5694 /mja13.10111 . • Morgan DJ, Dhruva SS, Wright SM, Korenstein D. 2016 Update on medical overuse: a systematic review. Jama Intern Med. 2016. doi: 10.1001/jamainternmed.2016.5381. • Male Hormones. Renew Youth Centers, LLC. Renew Youth. https://www.renewyouth.com. Accessed August, 26, 2017. • Pathophysiology of Disease: An Introduction to Clinical Medicine, Seventh Edition.New York, NY: McGraw-Hill; 2013. http://accesspharmacy.mhmedical.com.libproxy.uams.edu/content. aspx?bookid=961&Sectionid=53555704. Accessed November 15, 2016. • Bhasin S, Cunningham GR, Hayes FJ, et al., Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J ClinEndocrinolMetab. 2010:95(6):2536-2559. doi: 10.1210/jc.2009-2354.

30. References • LinneburSA, Wallace JI. Chapter 30. Erectile Dysfunction. In: Linn WD, Wofford MR, O'Keefe M, Posey L. eds. Pharmacotherapy in Primary Care.New York, NY: McGraw-Hill; 2009.http://access pharmacy.mhmedical.com.libproxy.uams.edu/content.aspx?bookid= 439&Sectionid=3996867Accessed July 24, 2016. • Chrousos GP. The Gonadal Hormones & Inhibitors. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015.http://accesspharmacy. mhmedical.com.libproxy.uams.edu/content.aspx?bookid=1193&Sectionid=69110111. Accessed July 24, 2016 • U.S. Food & Drug Administration. FDA drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. http://www.fda.gov/Drugs/ DrugSafety/ucm436259.htm. Published March 2015. Accessed October 10, 2016. • Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: seven coordinated trials of testosterone treatment in elderly men. ClinTrials. 2014; 11:362-75.

31. References • Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment on older men. N Eng J Med. 2016;374(7)611-624. doi: 10.1056/NEJMoa1506119. • Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 2017;317(7):717-27. doi: 10.1001/jama.2016.21044. • Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of testosterone levels with anemia in older men. JAMA Intern Med. 2017;177(4):480-90. doi: 10.1001/jamainternmed.2016. 9540. • Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017;317(7):708-16. doi:10.1001/jama. 2016.21043. • Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone. JAMA Intern Med. 2017;177(4):471-79. doi: 10.1001/jamainternmed.2016.9539.

32. References • BasariaS, Davda MN, Travison TG, Ulloor J, Singh R, Bhasin S. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. J GerontolA BiolSci Med Sci. 2013 February; 68(2):153-60. doi:10.1093/gerona/gls138. • Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Medicine. 2013;11:108. http://www.biomedcentral.com/1741-7015/11/108