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TTrials and clinical implications 2018
The testosterone trials (TTrials) originated with the Institute of Medicine 2003 recommendation to conduct a coordinated set of clinical trials to determine the efficacy of testosterone therapy in older men with low testosterone levels for no other reason that age, in order to determine if this population is appropriate for testosterone therapy.
There are many assumptions to keep in mind when discussing testosterone levels and aging. It is well known that testosterone levels - particularly the free testosterone fraction – decline with age. But is this due to normal aging or aging-related morbidities? There is no population of aging men on no medications with no morbidities that has been followed for decades, so we don’t know whether the aging related decline in testosterone is due to aging per see or aging-related morbidities.
The fundamental goal of the TTrials was to examine older men with low testosterone level for “no apparent reason other than age”.
The TTrials enrolled a population of men where 62% were obese, 72% had hypertension, 15% had a history of MI and 37% had type 2 diabetes. The therapeutic target was a testosterone level corresponding to the normal range for young men aged 19-40 years (280 to 873 ng/dL or 9.7 to 30.3 nmol/L). it should be noted that this is a numerical endpoint. In clinical practice, symptom relief is the endpoint.
In 2010 a notable randomized, double-blind, placebo-controlled study showed that testosterone treatment for 6 months in intermediate-frail and frail elderly men with low to borderline-low testosterone may prevent age-associated loss of leg muscle strength and improve body composition, quality of life, and physical function.1 There were no adverse cardiovascular evens in this study.1
In March 2015 FDA cautioned about using testosterone therapy for low testosterone due to aging because of alleged risk of MI and stroke. This was based on very flawed observational data.
The first TTrials report showed that in symptomatic men 65 years of age or older, testosterone therapy that elevates testosterone levels from moderately low to the mid-normal range for young men (aged 19 to 40 years) for 1 year significantly improves sexual function and mood and alleviates depressive symptoms, but has no significant effect on vitality or walking distance.2 Notably, there was no increase in cardiovascular events in the testosterone treated men. Surprisingly, during the follow-up year, there were 8 myocardial infarctions in the placebo group compared to 1 in the testosterone group.
Remark:For more information, see our report of this study:
The most discussed TTrial, the Cardiovascular Trial, was designed to investigate if testosterone treatment of older men with low testosterone slows the progression of noncalcified coronary artery plaque volume, assessed by coronary computed tomographic angiography (CCTA), an indicator of coronary atherosclerosis.3 Results showed that for the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204mm3 to 232mm3 vs 317mm3 to 325mm3, respectively; estimated difference, 41mm3 ). However, despite this there were no major adverse cardiovascular events in either the testosterone group or the placebo group.3 Also, an analysis of the individual plaque components revealed that the increase in non-calcified plaque volume was confined to the fibrous component of the plaque, which provides for plaque stability.4 This means that testosterone therapy may have resulted in stabilization of coronary plaques. Nevertheless, it is unknown whether plaque composition or plaque volume is of most importance in terms of clinical outcomes or “hard endpoints”.5
Remark:The suggestion that testosterone therapy may stabilize coronary plaques is consistent with both retrospective and prospective studies showing decreased major adverse cardiovascular events after testosterone therapy. For more information, see our reports of these studies:
It should be pointed out that the Cardiovascular Trial had several limitations. The placebo group had a greater volume of both calcified and noncalcified plaque at baseline. Furthermore, there are no prognostic studies of non-calcified plaque volume. Therefore the clinical implications of the Cardiovascular Trial are unknown.
Few studies have examined the effect of testosterone therapy on atherosclerosis in men. The TEEAM study showed that testosterone therapy for 3 years did not affect nether CAC not CIMT compared to placebo.6
Remark:For more information, see our report of this study:
Dr. Miner concludes his presentation commenting on the clinical quandary that testosterone therapy is facing in clinical practice, particularly on-label vs off-label prescribing of testosterone therapy, and the consequences of this for health insurance coverage and approval by drug regulation agencies such as the FDA.
Prof. Dr. Med. Marija Pfeifer Medical Faculty University of Ljubljana, Slovenia
Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FC. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010 Feb;95(2):639-50.Return to content
Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS; Testosterone Trials Investigators. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016 Feb 18;374(7):611-24Return to content
Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017 Feb 21;317(7):708-716Return to content
Arbab-Zadeh A, Fuster V. The myth of the "vulnerable plaque": transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J Am Coll Cardiol. 2015 Mar 3;65(8):846-855.Return to content
Ahmadi A, Stone GW, Leipsic J, et al. Prognostic determinants of coronary atherosclerosis in stable ischemic heart disease: anatomy, physiology, or morphology? Circ Res. 2016;119(2):317-329.Return to content
Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. 2015 Aug 11;314(6):570-81.Return to content