Testosterone CV safety

Bottom-line:

  • CV safety of testosterone replacement therapy has not been proven. Existing studies have not been able to convincingly rule-out a clinically important increase in CV events, & some studies demonstrate potential harm.

  • Theoretically, testosterone could also possibly reduce the risk of CV events in men with proven testosterone deficiency, though enthusiasm for this should be tempered by lessons learned from estrogen replacement therapy in post-menopausal women.

 

Context

  • "Low-T" (generally defined as late-onset hypogonadism or androgen deficiency syndrome) is a controversial syndrome generally presenting with bothersome symptoms with confirmation of low serum testosterone levels, such as:
    • Fatigue, depression, cognitive impairment, sleep disturbances
    • Sexual dysfunction (low libido, erectile dysfunction)
    • Somatic symptoms (decreased muscle mass & increased body fat, low BMD, anemia, hot flushing, decreased facial/body hair growth)
  • Cutoffs for "low" testosterone & indication for treatment differ by guidelines
    • European Association of Urology:
      • Total testosterone <8 nmol/L (230 ng/dL)
      • Free testosterone <225 pmol/L (65 pg/mL)
      • To be accurate, testing must be done between 7-11 am, or <3 h of waking in shift workers
  • Although guidelines generally recommend testosterone replacement therapy (TRT) in men with low serum testosterone levels and symptoms, evidence is generally weak, conflicting, & suggests clinically non-important benefits for sexual function, cognition & muscle strength

Best-available evidence for CV safety

Systematic reviews

  • Am J Med 2017
    • Search to Aug 2015 of PubMed, MEDLINE, Embase, CENTRAL, clinicaltrials.gov, hand-search
    • Included 34 RCTs, 10 observational studies (n=5451)
    • Risk of bias: Trials generally poorly reported, unclear risk of bias for most domains
    • P (Typical patient characteristics):
      • Men aged 50-60 y
      • Serum testosterone level <300 ng/dL to <480 ng/dL
      • 10/34 RCTs included pre-existing CVD, T2DM or metabolic syndrome
    • I/C: All compared 1 or more testosterone formulations to placebo, except 1 trial that compared TRT injection to patch
    • Outcomes in RCTs at follow-up ranging from 6 weeks to 3 years
      • All-cause death (20 RCTs): Peto odds ratio (OR) 0.88 (0.55-1.41), I^2 8%
      • MI (16 RCTs): Peto OR 0.87 (0.39-1.94), I^2 36%
      • Stroke (9 RCTs): Peto OR 2.17 (0.63-7.54), I^2 30%
    • Observational studies not meta-analyzed due to clinical & statistical heterogeneity. Results were variable:
      • 3 found TRT associated with increased CV risk
      • 5 found TRT associated with no difference or inconsistent effect on CV risk
      • 2 found TRT associated with decreased CV risk
  • Older systematic review (BMC Medicine 2013) found an increased CV risk with TRT, particularly in studies NOT sponsored by the pharmaceutical industry
    • 27 RCTs (n=2994)
    • CV events: OR 1.54 (1.09-2.18)
    • Sensitivity analysis (p=0.03 for interaction)
      • CV events in trials funded by pharmaceutical industry: OR 0.89 (0.50-1.60)
      • CV events in trials NOT funded by pharmaceutical industry: OR 2.06 (1.34-3.17)

Recent studies not included in above systematic reviews

  • JAMA 2017 RCT suggested accelerated atherosclerotic plaque buildup with TRT
    • Double-blind RCT of 170 men with mean age 71 years, serum testosterone <275 ng/dL & symptoms of low-T
    • Measured only surrogate outcome of plaque volume on coronary CTA: TRT increased total & non-calcified plaque volume vs placebo (+41 mm^3) over 1 year
    • No major adverse CV events occurred in either group over trial duration
  • NEJM 2016 RCT primarily evaluating symptomatic improvement with TRT vs placebo was underpowered to evaluate CV safety
    • Major adverse CV events: <2% in both groups
  • JAMA Internal Medicine 2017 cohort
    • Administrative cohort of 8808 men with mean age 58 years, diagnosis of androgen deficiency (3%) &/or serum testosterone <300 ng/dL (97%), <2% with prior CVD
    • At median 3.2 years, TRT (Rx filled at any time) versus no TRT (Rx never filled) was associated with a decreased risk of CV events: Hazard ratio (HR) 0.67 (0.62-0.73)
      • Results consistent with follow-up limited to very short-term (90 days), in those <65 or >65 years-old, with or without prior CVD

Main limitations in existing evidence

  • Incredibly underpowered for evaluation of clinical CV events (small sample size, short follow-up, patients at low risk of CVD)
  • Most trials at high/unclear risk of bias, leading to imprecise & inaccurate estimates of effect
    • In observational studies, a key source of confounding not adequately addressed is impact of socioeconomic status (wealthier patients more likely to experience good outcomes, also more likely to be able to afford relatively-expensive TRT)
  • No use of standardized outcome definitions in most trial