SAN DIEGO — Two new studies attest to the absence of cardiovascular risk from testosterone-replacement therapy, but, like all of the others, neither is the large, randomized, placebo-controlled trial that experts say would be necessary to answer the safety question once and for all.

In one two-part study involving both a retrospective cohort and nested case-control analysis of a large database of hypogonadal men, no increased risk for venous thrombotic events was seen with testosterone treatment.

In the other study, major adverse cardiovascular events were not increased with testosterone treatment in a retrospective analysis of data from two large, double-blind placebo-controlled efficacy trials of an investigational antiatherosclerotic drug in men with documented coronary disease or recent acute coronary syndrome.

Findings from the two analyses were presented March 7 at ENDO 2015, the annual meeting of the Endocrine Society, by Hu Li, MBBS, PhD, of Eli Lilly, and Salim Janmohamed, MBBS, of GlaxoSmithKline, respectively.

The new data come on the heels of two other studies — one observational, the other a meta-analysis —just presented at the American College of Cardiology (ACC) 2015 Scientific Sessions that also showed no increased cardiovascular risk among testosterone users.

All four studies seem to "contradict" the US Food and Drug Administration's warning earlier this month about the current overuse of testosterone-replacement therapy in men who do not have "low T" or in whom levels were not even tested, as well as the potential risks of myocardial infarction (MI) and stroke among men treated with testosterone-replacement therapy.

The FDA began investigating the link between testosterone therapy and adverse cardiovascular outcomes in January 2014 on the basis of two studies that linked the products with increased risks, one in men 65 and older, the other a cohort of Veterans Affairs patients who had multiple comorbidities and were undergoing coronary angiography.

The European Medicines Agency, however, in November 2014 concluded that there is "no consistent evidence" of an increased risk for cardiovascular problems with testosterone products.

A Broad Spectrum of Opinions

"This has become a popularized and controversial issue," Ronald Swerdloff, MD, from the University of California, Los Angeles, told Medscape Medical News at the ENDO 2015 meeting.

"The regulatory agencies have raised questions based upon some studies that suggest there may be adverse effects. But many other studies suggest there are no adverse effects, and there are mainly epidemiologic studies showing there may be adverse effects of low testosterone. So we have a broad spectrum of opinions on all sides of this."

He added, "In my opinion, it's okay to tell patients that we don't know whether there are going to be benefits or risks from long-term treatment with testosterone. It's perfectly okay to be careful who you treat with any medication and explain the benefits and risks of any treatment."

Others polled by Medscape Medical News disagree as to what is required going forward: some say a definitive safety study, like the Women's Health Initiative, is now needed, whereas others question whether such a trial is even possible.

Some information should be gleaned later this year, from a major multicenter 1-year efficacy study — the Testosterone Trial — funded by the National Institutes of Health (NIH), which is expected to shed light on the potential benefits of testosterone therapy vs placebo among 800 men aged 65 and older with serum testosterone levels less than 250 ng/mL.

The new FDA ruling and the Testosterone Trial results could push the idea of a definitive safety study forward, but results would still likely not be available for some years, and doctors need to know what to do now.

There is general agreement that it makes sense to follow current guidelines, such as those from the Endocrine Society, but unfortunately this still leaves much open to interpretation.

No Sign of CVD Risk

In the first study, reported at ENDO 2015 by Dr Li, the retrospective cohort analyses included a total of 102,650 testosterone-treated and 102,650 untreated hypogonadal men, with the two groups propensity-matched to ensure comparability.

The hazard ratio for idiopathic venous thromboembolism was 1.08 for all the testosterone-treated patients (P = .378) and did not differ significantly by administration type (ie, topical/gel, transdermal, or injection) or by age over 65 vs 65 or younger, Dr Li reported.

The second part of this, a nested case-control analysis of 2785 treated and 11,119 untreated patients, produced similar, nonsignificant findings, as did results from sensitivity analyses of events 60 and 120 days' postdiscontinuation and intention-to-treat analysis.

The other study used data from two international, double-blind, placebo-controlled randomized clinical trials involving 15,828 and 13,026 men and women with stable coronary heart disease and recent acute coronary syndrome, respectively. Both studies were designed to evaluate the potential effect of darapladib (GlaxoSmithKline), a lipoprotein phospholipase A 2 inhibitor, on ischemic events. (It had no effect.)

A total of 215 subjects — mostly American men — were testosterone users. At median follow-up periods of 3.7 and 2.5 years, respectively, the rates of adjudicated major adverse cardiovascular events — CV death, nonfatal MI, and nonfatal stroke — were lower among the testosterone users, with a hazard ratio of 0.48 for 12 months of exposure or less (P = .21) and 0.47 for more than 12 months of testosterone use (P = .02).

Although the number of testosterone users was small, "This retrospective analysis does not corroborate recent observational reports that testosterone therapy is associated with increased CV risk," Dr Janmohamed concluded.

What Will It Take to Prove CVD Safety?

The experts questioned by Medscape Medical News point out that all the various studies addressing this issue have involved different patient populations — some healthier than others at the outset — and all are subject to various biases, particularly the nonrandomized ones.

"These are all helpful studies that give preliminary information, but in order to answer the important question of whether any medicine has adverse effects, you need to have a carefully designed study to come to a real conclusion," Dr Swerdloff asserted.

Session moderator at the meeting, Joel S Finkelstein, MD, from Harvard Medical School, Boston, Massachusetts, told Medscape Medical News, "The only thing that will move this field forward is a study like the Women's Health Initiative. Nothing else. We can do all the retrospective studies we want; it's not going to move the field forward."

But whether or not a definitive safety study is even feasible — and if so, who would conduct it and how would it be funded — remain open questions.

And Adrian Sandra Dobs, MD, from the Johns Hopkins Clinical Research Network, Baltimore, Maryland, isn't so sure such a study is even possible.

"Who's going to do that study? It's going to cost billions of dollars to really do it….And there are a lot of ethics questions.…Are you not going to enroll anyone with an extremely low testosterone level because it would be unethical to randomize them to a placebo?

"Similarly, if they have a moderate decline, they would likely be an older population with age-related decline who might have some heart disease, so some might say it would be unethical to randomize them. I think a randomized, placebo-controlled study would be very difficult to do, and I think what we'll be left with is these large epidemiological-oriented studies."

But Dr Finkelstein believes that the new FDA ruling and the Testosterone Trial results could push the study idea forward: "There's so much pressure mounting now, with this massive overtreatment and now the FDA regulation, that I think there might be a consortium put together between industry and the government to fund a major trial."

Bernard Robaire, PhD, from McGill University, Montreal, Quebec, agrees. "What may drive it is industry's desire to have these drugs prescribed. The negative pressure to rule out harm….That might be what drives it," he told Medscape Medical News, but he added that it probably wouldn't be done through routine NIH funding competition. "It will be a special situation."

The results of the Testosterone Trial, expected later this year,should greatly inform the benefit side of the equation and will include some safety end points, but it's not powered to answer the ultimate question of whether testosterone-replacement therapy raises, lowers, or doesn't affect cardiovascular risk, Dr Swerdloff said.

What to Do While Waiting for Data?

Even if the definitive safety trial is undertaken, "it might take 20 years before the information comes out to settle the issue, so the problem for the physician is what to do in those [intervening] 20 years," he added.

The experts agree that it makes sense to follow current guidelines but that the recommendation to make a diagnosis of androgen deficiency only in men with "consistent symptoms and signs and unequivocally low serum testosterone levels" still leaves much open to interpretation.

And while following the 2010 Endocrine Society guidelines seems sensible, unknowns remain.

"The threshold testosterone level below which symptoms of androgen deficiency and adverse health outcomes occur is not known and may be age-dependent," the Endocrine Society guidelines state.

"Furthermore, the testosterone concentration below which testosterone administration improves outcomes is unknown and may vary among individuals and among target organs. Therefore, the available evidence does not support use of an arbitrary threshold for a testosterone level below which clinical androgen deficiency occurs and that confirms the diagnosis of hypogonadism in all patients."

Dr Robaire told Medscape Medical News, "I think you should not be treating to the T level. You should be treating the individual for what you need to treat them for. So you don't want to bring someone from low T to high T to protect from cardiovascular disease. There's no evidence for that. But treat the person for what the issues are — the symptoms."

However, Dr Finkelstein countered, "The symptoms of hypogonadism are no different from the symptoms of life in men. It's not like chest pain….If I complain of feeling tired and my sexual desire isn't what it was when I was 20, that completely overlaps with normal. Basing treatment on symptoms will never be effective. There isn't a distinct symptom complex."

He added, "The people with clear organic disease are easy.…For the guys with levels that are persistently below 150 [ng/mL], I think it's reasonable to give a diagnostic therapeutic trial. I'll often give 3 or 4 months of testosterone treatment and if they can come back and say it's made a marked difference, I'll continue….In the absence of clear safety data, I think it makes sense to be conservative in therapy. I'd rather be undertreating than overtreating."

On the other hand, Dr Swerdloff pointed out, "Many disorders, like high blood pressure, get worse as you age….Just because these things occur with increased frequency in an older age group doesn't mean it isn't worthy of concern. That would be like saying there's no point for anyone over age 65 to see a physician….The issue is, will the treatment of the hypogonadism benefit the individual?"

Dr Swerdloff, who was a coauthor on the Endocrine Society treatment guidelines, among others, recommends measurement of testosterone on two separate occasions as well a thorough evaluation to look for chronic conditions, such as type 2 diabetes, that can lead to low T.

"Chronic illness of all sorts can lead to low T. You need to have a comprehensive assessment in each patient." And importantly with regard to both efficacy and safety parameters, "document your conversation with the patient," he concluded.

The two studies were funded by Eli Lilly and GlaxoSmithKline. Dr Swerdloff reports grants and consulting from AbbVie, Clarus, Ardana, Besins Health, and Endo Pharma. Dr Li and coauthors are employees of Eli Lilly. Dr Janmohamed and coauthors are employees of GlaxoSmithKline. Dr Finkelstein has served as a principal investigator for Abbvie and is currently involved in a trial for Amgen. Dr Dobs is a clinical researcher for Endo Pharmaceuticals and Clarus; an advisory group member for Lipocine, Endo Pharmaceuticals, and AbbVie; and a consultant to AbbVie. Dr Robaire has no relevant financial relationships.

ENDO 2015: The Endocrine Society Annual Meeting. Abstract OR34-2 and Abstract OR34-4, presented March 7, 2015.