Written by Keen Meds · Reviewed by Licensed Clinical Providers · March 1, 2026
Key Insight: The Sharma 2015 Veterans study (European Heart Journal) followed 83,010 men and found that achieving testosterone normalization on therapy was associated with significantly lower rates of heart attack, stroke, and all-cause mortality compared to men whose testosterone did not normalize.
When men research testosterone replacement therapy, they often encounter conflicting headlines about cardiovascular risk. Some older observational studies suggested TRT raised heart attack risk. Others suggested it lowered it. The Sharma 2015 study, published in the European Heart Journal, is one of the most informative in this debate -- not because it is an RCT, but because of the particular insight it provides: the key variable for cardiovascular outcomes was not whether men received TRT, but whether testosterone actually normalized on therapy. This study of 83,010 male veterans is one of the largest observational datasets ever assembled on the topic, and its findings offer a clinically important signal that goes well beyond the simple "TRT safe or not" framing.
The Study: Design and Population
Ravi Sharma and colleagues at the Veterans Affairs system analyzed a retrospective cohort of 83,010 male veterans who had been diagnosed with testosterone deficiency. The study was published in the European Heart Journal in 2015.
The cohort was divided into three groups based on testosterone treatment status and testosterone response:
The first group consisted of men who received testosterone therapy and achieved normalization of testosterone levels on treatment. Normalization was defined as reaching a total testosterone above the deficiency threshold during follow-up.
The second group consisted of men who received testosterone therapy but did not normalize their testosterone levels -- they received the therapy but their levels remained low.
The third group consisted of men who were diagnosed with testosterone deficiency but did not receive any testosterone treatment.
This three-way division is the feature that makes the Sharma study analytically valuable. Most observational studies simply compare "treated" versus "untreated" men. Sharma's design allowed researchers to examine whether the effect of TRT depended on whether treatment actually worked in terms of raising testosterone levels.
The primary outcomes were major adverse cardiovascular events: heart attack (myocardial infarction), stroke, and all-cause mortality. Follow-up extended over several years, making this one of the longer observational datasets available.
The Key Finding: Normalization Was the Deciding Variable
The results demonstrated a clear dose-response pattern across the three groups.
Men who received TRT and achieved testosterone normalization had the lowest rates of heart attack, stroke, and all-cause mortality of any group.
Men who received TRT but did not normalize had outcomes that were not significantly different from men who received no treatment at all.
This finding is particularly important because it challenges the interpretation of some prior negative studies. If a study finds no benefit from TRT in observational data, one possibility is that some men in the "treated" group were inadequately treated -- their testosterone never actually normalized despite receiving therapy. Pooling these men with those who achieved normalization would dilute or erase any real benefit from effective treatment.
The Sharma study's dose-response logic is also relevant to the debate over causation. Observational studies cannot prove causation -- men who achieve normalization may differ from those who do not in ways that explain the outcome differences. However, a dose-response relationship is one of the classical criteria for inferring causation from observational data. If the benefit scales with testosterone normalization, that aligns with a biological mechanism rather than a simple selection artifact.
Why Testosterone Normalization Matters Biologically
The Sharma finding makes biological sense when you consider what testosterone does at the cellular and vascular level.
Testosterone has direct vasodilatory effects. It relaxes smooth muscle in arterial walls through several mechanisms, including calcium channel modulation. Low testosterone is associated with increased arterial stiffness and reduced endothelial function -- both precursors to cardiovascular disease.
Testosterone reduces visceral adiposity. Excess visceral fat is strongly linked to cardiovascular risk through its effects on inflammation, lipid profiles, and insulin resistance. Men who normalize testosterone tend to reduce visceral fat over time, which translates to reduced cardiovascular risk markers.
Testosterone has anti-inflammatory effects. Low testosterone is associated with elevated inflammatory markers including C-reactive protein and interleukin-6. These markers are independently associated with cardiovascular events. Normalizing testosterone reduces the inflammatory burden.
Testosterone supports cardiac muscle function. Androgen receptors are present in cardiac tissue. Testosterone deficiency is associated with reduced cardiac output and contractile function in some studies, particularly in men with heart failure.
The Sharma data suggests that receiving a prescription for TRT is insufficient -- the clinical target is confirmed normalization of testosterone levels. This has direct implications for how TRT monitoring should be conducted.
Contextualizing Sharma Against the Vigen Study
In 2013, a study by Vigen and colleagues published in JAMA suggested that testosterone therapy was associated with increased rates of adverse cardiovascular events. That study attracted widespread attention and contributed to FDA safety warnings.
The Vigen and Sharma studies are both observational, both based on VA healthcare data, and both involve men with testosterone deficiency. Yet their conclusions point in opposite directions. The most critical difference is how each study handled the treatment variable.
Vigen categorized all men who received any TRT prescription as "treated," regardless of whether testosterone levels normalized or whether they were actually taking the medication. The Sharma study separated treated men into those who normalized and those who did not. This distinction fundamentally changes what the analysis measures.
Additionally, Sharma's cohort was much larger (83,010 vs. approximately 8,700 in Vigen), providing greater statistical power to detect meaningful differences. The specific populations and definitions also differed in ways that affect comparability.
This does not mean Vigen was wrong and Sharma was right -- observational data has inherent limitations regardless of size. But it illustrates why understanding study design is essential to interpreting the headline results of testosterone and cardiovascular risk.
Frequently Asked Questions
Does the Sharma study prove that testosterone therapy protects the heart?
No observational study can prove causation. The Sharma study demonstrates a strong association between achieving testosterone normalization and improved cardiovascular outcomes in a large cohort of male veterans. The dose-response pattern strengthens the biological plausibility, but a randomized controlled trial is required to establish causation definitively. The TRAVERSE trial (2023) later provided that RCT evidence, confirming cardiovascular safety.
Why did men who received TRT but did not normalize have similar outcomes to untreated men?
The Sharma finding suggests that the cardiovascular benefit in the treated group was concentrated in men who actually reached therapeutic testosterone levels. Men who received therapy but remained testosterone-deficient experienced the biological effects of testosterone deficiency despite being on treatment -- which could reflect inadequate dosing, poor adherence, or individual pharmacological variation.
What does "testosterone normalization" mean in practice?
In the context of the Sharma study, normalization refers to achieving a total testosterone level above the deficiency threshold during follow-up monitoring. In clinical practice, the target range for TRT is generally 400 to 700 ng/dL (mid-physiological range). Monitoring testosterone levels at 3 months and periodically thereafter is standard clinical practice and the means by which confirmed normalization is established.
How often should testosterone levels be checked on therapy?
Standard monitoring includes a testosterone level check at approximately 3 months after starting therapy to confirm you have reached a therapeutic range. Annual monitoring is then appropriate for stable patients. If your level has not normalized, your provider may adjust your dose or formulation. Monitoring also includes hematocrit and PSA checks.
What This Means for Your Treatment Decisions
The Sharma study reinforces that testosterone monitoring is not optional -- it is a critical part of safe and effective TRT. Achieving confirmed testosterone normalization, not just starting therapy, appears to be the threshold for cardiovascular benefit. This is one of the reasons Keen Meds builds lab review into its clinical process.
Keen Meds connects you with licensed clinical providers for a telehealth evaluation and lab review. If your testosterone is clinically low, you may qualify for Testosterone Spray Rx.
