This is an interesting study suggesting that testosterone increases non-calcified plaque. While this study does demonstrate some truth to this statement, there appear to be multiple confounding issues.
Objective: They wanted to see if giving testosterone (topical gel) slows the development or progression of non-calcified coronary artery plaque.
Design, setting, and participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.
Intervention: Testosterone gel vs placebo for 12 months. Testosterone dose was adjusted to maintain the testosterone level in the normal range for young men (19-40 years of age)
Main outcomes and measures: Noncalcified coronary artery plaque volume, as determined by Coronary CT angiography was the primary outcome. Coronary Artery Calcium Score and Total Coronary Artery Plaque Volume were both secondary outcomes.
Results: 138 (73 testosterone treatment and 65 placebo) completed the study and were available for the primary analysis. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis.
Primary outcome: There was a significantly greater increase in noncalcified plaque volume from baseline to 12 months in the testosterone group compared to the placebo group (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003).
Secondary outcomes: the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.
Conclusions and relevance: “Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography.”
At first glance, it looks as though patients on testosterone replacement may be at higher risk of non-calcified coronary artery plaque progression. However, there are 400 known risk factors for cardiovascular disease, non of which were controlled in this study. Randomization is supposed equalize the 2 groups but there were clear differences between the 2 groups at baseline.
Baseline non-calcified plaque in the testosterone group was 204 mm3 and 317 mm3 in the placebo group. Baseline calcified plaque in the testosterone group was 272 mm3 and 499 mm3 in the placebo group. Coronary Artery Calcification Score at baseline in the testosterone group was 255 and 494 in the placebo group. These are significant differences. The testosterone treatment group clearly had significantly less coronary artery disease by all 3 metrics compared to placebo. There is no explanation for the differences.
There are clearly confounding issues in this study but it is difficulty to ascertain the exact reasons. Multiple other studies show cardiovascular disease benefit with testosterone replacement which, to me, further magnifies the confusion with this study.
- 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):708-716.