Although prevalence of testosterone deficiency (TD) is high and growing, the disorder often remains undiagnosed and thus, untreated. Factors such as age, obesity, and other chronic diseases all contribute to this prevalence of TD. Several studies show that the main patient group affected by low testosterone levels is men aged 40 and older, particularly those who are suffering from chronic diseases such as type 2 diabetes (T2D) or obesity. But is there really a connection between testosterone and metabolic and cardiovascular diseases, or is the relationship coincidental?

Treatment of TD is typically testosterone replacement therapy (TRT). Patients can receive testosterone in a variety of currently marketed forms: oral tablets, subcutaneous injections, buccal sprays, or the most popular, transdermal formulations. At present, gels and patches are the market-leading formulation in the low testosterone market with AbbVie garnering the highest sales. Sales numbers for AbbVie's Androgel have shown strong annual growth since launching in 2000 to approximately $ 1.1 billion in 2012. However, Decision Resources forecasts the market landscape will change dramatically over the next few years, as major patents expire and promising candidates in the R&D pipeline such as Clarus's CLR-610, Repros's Androxal, and Novartis BGS649 launch onto the market. More information about current and future products and their forecasted performance can be found in the Decision Resources's Pharmaview database.

There are two options to measure testosterone levels in the body, total testosterone and free testosterone. A study by Kapoor et al. published in Diabetes Care 2007 examined 355 men with T2D and discovered that 31 percent of the subjects also suffered from overt hypogonadism. This means either a total testosterone level <8 nmol/L or bioavailable testosterone <2.5 nmol/L. Another 54 percent of the men had a total testosterone level between 8 and 12 nmol/L or a bioavailable testosterone level between 2.5 and 4 nmol/L, which means possible hypogonadism. Ultimately these studies suggest that about one-third of all men diagnosed with T2D are also hypogonadal. Although more studies are needed to get reliable numbers, this demonstrates the significance of this patient population, and there are also a high proportion of patients who remain undiagnosed.

The link between TD and T2D is widely acknowledged and has been demonstrated in a number of small-scale clinical studies. However, studies such as the one by Grossmann are good examples of a lack of certainty over whether low testosterone is a biomarker that coexists with diabetes (because of common risk factors) or a direct consequence of progression of T2D. Furthermore, high serum testosterone levels can have a vasodilatory effect on the coronary arteries and may therefore help to prevent cardiovascular disease (CVD) in men. Among thought leaders, opinions about the linkage between low testosterone and metabolic and cardiovascular diseases vary markedly. Yet, the consensus is that larger long-term trials are required to clarify these relationships.

Several cross-sectional meta-analyses like the ones by Ding et al. or Corona et al. focused mainly on measurement of testosterone and blood sugar levels and found that diabetic men had consistently lower testosterone levels than nondiabetic control groups. Together the studies being looked at included approximately 6500 men and 7000 woman. Another study by Dhindsa et al. demonstrated that hypogonadotropic hypogonadism occurs commonly in the 103 analyzed T2D patients, but total testosterone levels in the body correlate inversely with weight and BMI, which are also risk factors for T2D. On the other hand the study results revealed a prevalence of hypogonadism in the normal BMI group of 31.3 percent. None of the clinical studies proved conclusively whether the association between diabetes and free testosterone levels is a primary or secondary relationship.

The significance of testosterone levels in patients with metabolic and cardiovascular disorders is clear but the key question remains unanswered: Is testosterone just a marker of general health and secondarily linked to the previously described co-morbidities, or could it actually be an underlying cause of these conditions? This controversy and the remaining unmet need in the low testosterone market present opportunities both for existing players to garner greater sales and for new companies to enter the space through the development of new therapies.

Stefanie Matlok is a data analyst with the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources.

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