Effects of 6-year Long-Term Testosterone Replacement Therapy (TRT) in Patients with ‘‘Diabesity’’
March 6th 2014 FDA approved Aveed for treatment of male hypogonadism, aka testosterone deficiency. Aveed is a long-acting form of injectable testosterone called testosterone undecanoate. In Europe, testosterone undecanoate (under the name Nebido) has a long successful TRT track record for treatment of testosterone deficiency and its consequences (especially obesity, the metabolic syndrome and diabetes).[2-16]
In contrast to shorter acting forms of testosterone (e.g. cypionate), testosterone undecanoate only needs to be injected every 6 to 12 weeks, and thereby offers practical benefits to patients. (Comment: for Nebido (1000 mg per 4 ml) the initial interval is 6 weeks, followed by intervals of 10-14 weeks; for Aveed (750 mg per 3 ml) the initial interval is 4 weeks, followed by 10-week intervals).
Five days after the FDA approval a notable and impressive 6-year long TRT study was published, confirming the health benefits of TRT that have previously been found in shorter term studies... 
The term “diabesity” was coined in the early 1970s to describe the occurrence of obesity and diabetes in the same individual. Excessive amounts of body fat, especially abdominal (visceral) fat accumulation, is a well documented strong risk factor for insulin resistance and development of type-2 diabetes and cardiovascular disease.[18-26]
More and more studies are showing that testosterone deficiency contributes to development of obesity (both general and abdominal), insulin resistance, metabolic syndrome, type-2 diabetes and muscle loss. [27-32] In line with this, a growing number of intervention studies have demonstrated that TRT improves these outcomes.[2, 3][4, 28, 33-43]
Several recent 5-year long-term studies reported that TRT results in marked and significant weight (fat) loss, reduction in waist circumference and BMI, as well as improvements in blood cholesterol parameters and reductions in fasting glucose, HbA1c, CRP (in inflammatory marker) and liver enzymes.[3-5, 7]
Most recent long term study proving efficacy and safety of TRT use for 6-year
The longest study reported to date was conducted by a research group in Germany led by Dr Farid Saad, one of the most prominent worldwide leaders in the field of TRT research. This study was published March 11th, 2014 in the International Journal of Endocrinology.
Subjects were obese hypogonadal men with type-2 diabetes, aged between 41 and 73 years. All subjects had sub-normal total testosterone levels, mean 257 ng/dL (8.9 nmol/L), range 47-345 (1.63–11.79 nmol/L) and at least mild symptoms of hypogonadism assessed by the Aging Males’ Symptoms scale (AMS).
All men received treatment with testosterone undecanoate 1000 mg (Nebido, Bayer Pharma, Berlin, Germany), administered at baseline and at 6 weeks, and thereafter every 12 weeks for up to 72 months.
Waist circumference (WC) was measured midpoint between the iliac crest (top of the hip bone) and the lowest rib.
All 156 subjects were followed for at least one year, 146 for at least two years, 136 for three years, 114 for four years, 105 for five years, and 69 for six years.
Total Testosterone Levels during the 6-Year Period of Testosterone Treatment
Total testosterone levels showed a significant rise from 257 ng/dL (8.9 nmol/L) at the beginning of therapy to above 461 ng/dL (16 nmol/L) within the first year of therapy, and this physiological level remained constant throughout the course of treatment.
Figure 1 demonstrates the measured reduction in waist circumference subsequent to testosterone therapy in obese diabetic men. Waist circumference dropped from an average from 44.9 in (minimum 35 in, maximum 58 in) [114 cm (minimum 89 cm, maximum 148 cm)] to 40 in (minimum 32 in, maximum 47 in) [102 cm (minimum 82 cm, maximum 121 cm)] with a mean reduction of 4.6 in (11.56 cm) over the entire 6 year treatment period. The reduction in waist circumference was statistically significant at the end of each year compared to the previous year over the first five years, even at the end of six compared to five years.
Figure 2 shows the effects of TRT on body weight over the course of 6 years of therapy. Body weight decreased from an average of 249 lb (minimum 191 lb, maximum 311 lb) [113 kg (minimum 87 kg, maximum 141 kg) to 213 lb (minimum 176 lb, maximum 262 lb) [97 kg (min 80, max 119)] with a mean loss of 38.6 lb (17.5 kg) over the course of treatment. This decrease in body weight was statistically significant at the end of each year compared to the previous year over the first five years, even at the end of six compared to five years.
Percentage Change in Body Weight
A marked and significant decrease in percentage body weight was noted over the course of testosterone therapy. Over the entire 6-year observation period, patients lost 15% of their initial body weight (Figure 3). After one year, patients had lost 3.1% of their initial weight, after two years, 6.8%, after three years, 9.6%, after four years, 11.8%, after five years, 13.6%, and after 6 years, 15%. These successive yearly changes were statistically significant compared with baseline.
Blood Glucose Levels
There was a significant gradual decrease in fasting blood glucose from 128.37 ± 31.63 mg/dL (7.06 ± 1.74 mmol/L) to 101.55 ± 17.02 mg/dL (5.59 ± 0.94 mmol/). The decrease was significant after one year, further declined after two years (non-significant compared to level after year 1), and then reached a plateau with another slight but statistically significant decrease at five years compared to four years. Over the course of 6 year testosterone treatment, fasting blood glucose decreased by 27.14 ± 2.48 mg/dL (1.49 ± 0.14 mmol/L).
Hemoglobin A1c (HbA1c) Levels
The decrease in fasting blood glucose was accompanied by a marked decrease in HbA1c from 8.1% to 6.1% with a mean change of 1.9% at the end of the 6 year long testosterone treatment period.The decrease in HbA1c was progressive and statistically significant after one year, between two years and one year, between three and two years, between four and three years, and between five and four years and approached significance between six and five years.
Blood Cholesterol/Lipid Profiles Testosterone therapy improved lipid profiles as demonstrated with increase in high density lipoprotein cholesterol (HDL-C) by 35 ± 5%, significant reductions in total cholesterol by 32 ± 1.4%, low density lipoprotein cholesterol (LDL-C) by 25.9 ± 1.6%, and triglycerides (TG) by 30 ± 2%.
The mean changes in lipid profiles were gradual and progressive and were significant at each year when compared to baseline levels, reaching plateaus between three and four years. The ratio of total cholesterol to HDL cholesterol improved from 6 to 3. These changes reached a plateau after three years with further slight but not statistically significant decreases.
Blood Pressure, Inflammatory Status and Liver Function
In addition, testosterone treatment significantly reduced blood pressure, CRP (an inflammatory marker) and levels of the liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT), suggesting a reduction in liver fat content, a reduced inflammatory response, and improvement in liver function.
Impact of Baseline Total Testosterone below versus above 231 ng/dL (8 nmol/L)
An analysis was made to see whether there were any differences in response among patients who at baseline had total testosterone levels below 231 ng/dL (8 nmol/L) versus those with levels between 231 ng/dL and 346 ng/dL (8 nmol/L and 12 nmol/L). It was found that obese diabetic men in the higher testosterone category responded to testosterone treatment equally well as those with lower baseline testosterone levels.
No adverse events were reported in patients treated with testosterone for up to 6 years.
The study authors concluded that long-term TRT for up to 6 years results in significant and sustained improvements in weight, type-2 diabetes, and other cardiometabolic risk factors in testosterone deficient obese, diabetic. This study clearly demonstrates that TRT confers tremendous improvements in metabolic parameters and body composition, and may play an important role in the management/treatment of obesity and diabetes (diabesity) in men with testosterone deficiency.
Critics of TRT often state that there are no long term safety and efficacy studies on TRT. This 6-year long TRT study and previous 5-years long studies [3, 4, 6, 7]blatantly refute those claims. Several of results from the above outlined 6-year long TRT study deserve special mention: 
First, this 6-year long study clearly demonstrates that TRT confers long term effects for the duration of treatment. Therefore, the response to a short term 3-month therapeutic trial of TRT, which has been suggested to be used as part of the diagnosis of hypogonadism , will not allow enough time for full expression of all the beneficial effects that have been documented in longer term TRT studies.[3-7, 44] For example, in the 6-year study outlined above, it took 1 year before significant and marked reductions were seen in waist circumference, weight, fasting glucose and HbA1c.Further support for the importance of allowing enough treatment time comes from an analysis of the onset of effects of TRT and time span until maximum effects are achieved.This analysis concluded that improvements in blood cholesterol/lipids and glycemic control may need up to 12 months for full expression.Another important parameter when discussing TRT and time course of treatment is PSA (Prostate-Specific Antigen). PSA and prostate volume initially rises marginally, but it reaches a plateau at around 12 month (further increase should be related to aging rather than therapy).This is a normal response and the initial PSA elevation should not be an indication to discontinue TRT too soon, if there are no contra-indications. Prostate growth is extremely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels.A short-term TRT treatment will not allow testosterone saturation of the prostate and PSA to the plateau.
Second, TRT with testosterone undecanoate 1000 mg at baseline, 6 wk and every 12 wk thereafter restored physiological testosterone levels within the first 12 months, and testosterone levels were maintained at this dosage regimen throughout the entire 6-year period. It should be noted that different testosterone preparations (e.g. testosterone cypionate, gel, pellet, oral) require different dosages and administration schedules in order to achieve a give target testosterone level.
Third, over the course of 6 years, TRT markedly and significantly reduced total cholesterol and LDL levels, and this reduction was very pronounced and sustained over the entire 6-year period of testosterone treatment. More importantly, TRT not only reduced the levels of total cholesterol and LDL, but also resulted in significant increases in HDL levels. Moreover, the ratio of total cholesterol to HDL cholesterol dropped from over 6 to below 3.5. As the total cholesterol to HDL ratio is a risk factor for cardiovascular disease [48, 49],this marked drop is notable.
Fourth, another important observation in this study was the marked and significant reduction in triglycerides (blood fats) in response to TRT. Since intra-abdominal (visceral fat) storage is driven by accumulation of triglycerides, this could help explain the reduction in waist circumference. In addition, the great reduction in triglycerides, especially when combined with the elevation in HDL, is an indication of an increased LDL particle size (i.e. a reduction in the atherogenic LDL fraction which is comprised of small LDL particles).A decreased triglyceride/HDL ratio also indicates improved insulin sensitivity [50-54]. Thus the reduction in triglyceride/HDL ratio seen in the 6-year long testosterone replacement study is in line with previous research showing that TRT improves insulin sensitivity in testosterone deficient men. [2, 55]
Fifth, the percent reduction in lipid levels (total cholesterol, LDL, and triglycerides) was close to 30%, which is a value similar to that attained by use of statins in men with abnormal blood lipids (dyslipidaemia).
Sixth, it is notable that men with both very low and borderline low total testosterone levels responded equally well to this 6-year long-term testosterone treatment.
Finally, this study clearly shows that different outcomes plateau at different time points. For ex. the significant improvements in blood cholesterol and triglycerides (lipids) reached a plateau after 3-4 years of TRT, while the decrease in HbA1c was progressive and statistically significant up to five years of testosterone treatment. Importantly and interestingly, the reductions in waist circumference and body weight (and percentage change in body weight) were statistically significant at the end of each year compared to the previous year over the first five years, and even at the end of the sixth year compared to fifth year. This is an unusual and remarkable finding, as obesity interventions (both drugs and lifestyle changes) commonly are most effective the first year, and thereafter progressively lose their efficacy.[57-59]As this 6-year long study demonstrates, testosterone treatment excels in this regard. Let's hope in the near future this information will reach doctors working with patients who are sedentary, obese and suffer from cardio-metabolic complications.
Did your doctor tell you that there isn't enough long-term safety and efficacy data to support the use of TRT? If so, do yourself a favor and get another doctor who is informed on the latest advances in testosterone research and men's health.
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