Effects of testosterone therapy for up to 10 years on obesity and metabolic parameters
Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study.
Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Andrologia 2016:Jan 14 [Epub ahead of print]
While it is well documented that testosterone levels decline in aging men, recent studies show that obesity and impaired general health can be more influential causes of testosterone deficiency than chronological age per se.1,2
Here we present real-life results from a registry study which investigated the effects of continuous long-term testosterone therapy on anthropometric, endocrine and metabolic parameters in obese hypogonadal men, for up to 10 years.3
What is known
Testosterone deficiency is associated with substantially higher risks of all-cause and cardiovascular mortality4,5, and normalization of testosterone levels with testosterone therapy reduces incidence of myocardial infarction and mortality, both in diabetic6,7 and non-diabetic men.8,9
Risk factors for testosterone deficiency include obesity, advanced age, the metabolic syndrome and a poor general health status.10 Among these, obesity is an especially strong risk factor for testosterone deficiency.1,2 In addition, testosterone deficiency is a risk factor for obesity. This creates a vicious circle where obesity feeds testosterone deficiency and testosterone deficiency feeds obesity.
Testosterone therapy has a number of beneficial metabolic effects and improves body composition, body fat distribution and metabolic factors11-13, and thus may be a powerful tool in breaking the obesity-hypogonadal obesity cycle.
What this study adds
In this registry study, 1000 mg injections of testosterone undecanoate in 12-week intervals were continuously given to 115 men with a maximal follow-up of 10 years. The composition of these patients was as follows: 115 men were treated for a minimum of 4 years, 114 for 5 years, 97 for 6 years, 70 for 7 years, 57 for 8 years, 48 for 9 years and 23 for 10 years. Mean treatment time was 7.6 years.
Total testosterone levels increased from 7.8 nmol/L (226 ng/dL) to trough levels (measured prior to the following injection) of 19.7 nmol/L (568 ng/dL; P < 0.0001 vs. baseline, statistical significance vs. previous year for the first 3 years) free T increased from 144.8 to 461.1 pmol/L, and SHBG decreased from 40.1 to 33.1 nmol/L (P < 0.0001 for both).
Waist circumference decreased progressively from 107 to 92 cm. The decrease was significant vs baseline (P < 0.0001) and significant vs previous year for the first 7 years. The reduction in waist circumference was 12%. Body weight decreased from 97.3 to 84.6 kg. The decrease was statistically significant vs baseline (P < 0.0001) and significant vs previous year for the first 8 years.
Mean BMI decreased from 31 to 27. The decrease was statistically significant vs. baseline (P < 0.0001) and significant vs. previous year for the first 8 years. Weight reduction was progressive and accumulated to 18.5% (minimum - 6.19% and maximum - 31.97%) after 10 years.
There were major improvements in the lipid profile. The total cholesterol:HDL ratio – a cardiovascular risk marker 14 - improved from 6.6 to 3.1 (P < 0.0001 vs. baseline, statistical significance vs previous year for the first 6 years). The triglyceride:HDL ratio, a surrogate marker of insulin resistance 15, improved from 6.2 to 2.8 (P < 0.0001 vs. baseline, statistical significance vs previous year for the first 2 years).
The yearly changes in lipids are presented in figure 1 and figure 2. The reductions in non-HDL cholesterol were significant vs. previous year for the first 7 years.
Systolic blood pressure decreased from 135 to 120 mmHg (P < 0.0001 vs. baseline, statistical significance vs. previous year for the first 3 years), and diastolic blood pressure decreased from 83 to 74 mmHg (P < 0.0001 vs. baseline, statistical significance vs. previous year for the first 5 years). A decline in CRP from 1.39 to 0.62 mg/dL (P < 0.0001 vs. baseline, with the main reduction in the first treatment year (Fig. 4e) was also observed.
Fasting glucose decreased from 111 to 77 mg/dL (P < 0.0001 vs. baseline), with the main reduction occurring during the first treatment year. HbA1c declined from 6.38 to 5.42% with mean measures <6% from year 2 onward (P < 0.0001 vs. baseline, statistical significance vs. previous year for the first 3 years. Of the 115 analysed patients, 67 (58.3%) were diagnosed with pre-diabetes or had a diagnosis of type 1 diabetes mellitus (1.7%) or type 2 diabetes (26.1%) at baseline.
No major adverse cardiac event occurred during the entire observation time.
The study by Yassin et al. solidifies previously reported reductions in waist circumference, body weight, and BMI with testosterone therapy, which we covered in previous editorials:
Effects of long-term testosterone treatment on weight and waist size in men with obesity - observational data from two registry studies
Testosterone and weight loss - the evidence
Two particularly notable findings by Yassin et al. are the marked reductions in non-HDL cholesterol and remnant cholesterol. Non-HDL-C better reflects the increased cardiovascular risk associated with high apoB levels and small LDL particle size, which are hallmarks of obesity.16 When triglyceride levels exceeds 150 mg/dL – as is commonly seen in patients with the metabolic syndrome, obesity, diabetes and cardiovascular disease - LDL particle number, apoB and VLDL levels increase without concomitant elevations in LDL-C.14,16,17 Thus, non-HDL-C is more reflective of atherogenicity in persons with elevated triglycerides.18 This constellation of increased triglyceride (TG), reduced HDL-C, increased small dense LDL particles, and increased remnant cholesterol levels (primarily VLDL, see below), is known as atherogenic or ‘‘adiposopathic” dyslipidemia.19
The superiority of non-HDL-C over LDL-C has been proven in multiple studies. A meta-analysis demonstrated that on-treatment levels of non-HDL-C are more strongly associated with future risk of cardiovascular events than either apoB or LDL-C.20 In an analysis of men enrolled in NHANES II, increasing BMI was associated with higher triglyceride, total and non-HDL cholesterol levels, and lower HDL-C.21 In middle-aged and older men, LDL-C did not vary with BMI and the elevation in total cholesterol was due mainly to an increased non-HDL-C level.21 NHANES III also showed that non-HDL-C is a significantly stronger correlate with BMI than LDL-C.22 While total cholesterol and LDL-C generally correlate on a population level, this correlation weakens at higher body weights where VLDL-C (which is included in the non-HDL-C measure) makes a larger contribution to total cholesterol.23 Similarly, accumulation of visceral adipose tissue - which drives the metabolic syndrome and diabetes - is associated with the lipoprotein profile of obesity with a normal LDL-C despite elevated level of atherogenic lipoproteins cardiovascular risk.24
The EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk prospective population study followed 21,448 participants without diabetes or CHD between age 45 and 79 years for 11 years. A total of 2,086 participants developed CHD during follow-up.25 In this large study, which is representative of the contemporary Western population, it was found that non-HDL-C, TG, and the TC to HDL-C ratio were more strongly associated with risk of future CHD than was LDL-C.25 Interestingly, the increased risk associated with elevated non-HDL-C levels, TG levels, or with an elevated TC to HDL-C ratio was present in any given LDL-C category, and especially in participants with low LDL-C levels.25 In this study, LDL-C did not provide any additional risk for CHD to non-HDL-C, whereas at any given LDL-C level, non-HDL-C levels were associated with higher CHD risk.25 Similar results were reported in an earlier study which found that within each LDL-C category (<130 mg/dl, 130–159 mg/dl, >160 mg/dl), non-HDL-C (<160 mg/dl, 160–189 mg/dl, >190 mg/dl) was additionally predictive of CAD event rates, but within each non-HDL-C category, LDL-C was not.26 In these patient populations - which comprise a large proportion of the general population - reliance on LDL-C as a risk indicator and therapeutic target in these populations is misleading. Even in normal weight men, when non-HDL-C and LDL-C are mutually adjusted, only non-HDL-C is predictive of CHD.27
In the study by Yassin, non-HDL levels dropped from 208 mg/dL to 167 mg/dL to 116 mg/dL after 1 and 10 years of testosterone therapy. This is a reduction of 20% and 45%, respectively. LDL-C dropped from 157 mg/dL to 136 mg/dL to 98 mg/dL, with corresponding percentage reductions of -14% to -37%. In non-obese men, testosterone therapy results in a less reduction in LDL. This shows that testosterone therapy has a greater effect on non-HDL than LDL.
Several society guidelines for management of dyslipidemia for cardiovascular disease have recently added non-HDL as a primary treatment target. The International Atherosclerosis Society (IAS) Position Paper on the management of dyslipidemia considers non-HDL-C as an alternative to LDL-C as target of therapy, and actually favors adoption of non-HDL-C as the major target of lipid-lowering therapy.18 The IAS expects that in future guidelines non-HDL-C will replace LDL-C as the best treatment target.
The European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) guideline states that non-HDL-C can provide a better risk estimation compared with LDL-C, in particular in patients with the metabolic syndrome or diabetes, who commonly have elevated triglyceride levels.28
Notably, the National Lipid Association (NLA) states that while non-HDL-C and LDL-C are co-primary treatment targets, non-HDL-C is the superior treatment target for modification.19 Non-HDL-C levels and change during treatment of dyslipidemia are more strongly associated with reduced risk for atherosclerotic coronary heart disease (CHD) than changes in LDL-C, or on-treatment levels of LDL-C.19
Another result from this study to be highlighted is the reduction in remnant cholesterol levels. Remnant cholesterol is all plasma cholesterol not found in LDL and HDL, that is, in all triglyceride-rich lipoproteins.29 In the fasting state, this constitutes cholesterol in very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), whereas in the non-fasting state, cholesterol in chylomicron remnants is also included.29 However, even in the non-fasting state, calculated remnant cholesterol is mainly cholesterol in VLDL and IDL.29 Remnant cholesterol can be calculated as total cholesterol minus LDL-C minus HDL-C.30
For calculated non-fasting remnant cholesterol, it has been shown that those in the top versus bottom quintile (>1.1 versus <0.4 mmol/L; >43 versus <15 mg/dL) have 2.3-fold risk of ischemic heart disease.31 In the Copenhagen City Heart Study and Copenhagen General Population Study, including 82,890 individuals, the risk of MI increased continuously with increasing remnant cholesterol, even when the analysis for remnant cholesterol was adjusted for LDL cholesterol.32 When compared with individuals with non-fasting remnant cholesterol levels <0.5 mmol/L (<19 mg/dL), the risks for MI were 1.8-fold for a remnant cholesterol level of 0.5 to 0.99 mmol/L (19-38 mg/dL), 2.2-fold for 1.0 to 1.49 mmol/L (39-58 mg/dL), and 3.0-fold for remnant cholesterol ≥1.5 mmol/L (58 mg/dL).32 When examining all-cause mortality, the risk increased continuously with increasing remnant cholesterol concentrations, but not with increasing LDL-C.32 When compared with individuals with non-fasting remnant cholesterol levels <0.5 mmol/L (19 mg/dL), the risk for all-cause mortality was 1.4-fold in individuals with remnant cholesterol level of ≥1.5 mmol/L (58 mg/dL).32
These results agreed with previous observations in the Copenhagen City Heart Study that increasing plasma triglycerides (as a marker of remnant cholesterol) were associated with increasing all-cause mortality in individuals in the general population, whereas this was not the case for increasing levels of total cholesterol (as a marker of LDL cholesterol).33
Even in statin trials, elevated remnant cholesterol seems to be associated with residual risk of arteriosclerotic cardiovascular disease (ASCVD).34,35
Genetic population-wide studies have demonstrated that elevated triglyceride-rich lipoproteins are causally associated with atherosclerotic cardiovascular disease, whereas low HDL cholesterol is not.31,36 The causal risk increase for a 1-mmol/L (39 mg/dL) genetic increase of non-fasting remnant cholesterol was 2.8-fold, with a corresponding observational estimate of 1.4-fold.31 Importantly, when the effect size for the causal estimate is much larger than the observational for the same increase in a lipoprotein, then this represents additional strong evidence for a causal life-long exposure.29
In the study by Yassin, percentage reductions in remnant cholesterol levels were -38% after 1 year and -66% after 10 years. This reduction was markedly greater than that of both LDL and non-HDL. This is concordant with the high baseline triglyceride level in obese hypogonadal men. Hence, when evaluating the efficacy of testosterone therapy on the lipid profile, attention should be given to non-HDL, and especially remnant cholesterol. Considering the data from the Copenhagen population studies, the marked improvements in remnant cholesterol with testosterone therapy likely explain – possibly to a large part – the reduction in mortality that has been observed with testosterone therapy.6,7,9
Another notable aspect of Yassin’s study is its real-life nature. It is widely accepted that randomized controlled trials (RCTs) are the gold standard for demonstrating the efficacy of a given therapy (i.e. effect under ideal circumstances). Real-life studies, on the other hand, complement this by demonstrating effectiveness (i.e. true benefit to patients in routine practice).37
Applicability of RCT results to daily clinical practice can be limited for several reasons; the patients selected to participate in RCTs may be different from those in routine practice, and RCTs are often designed to detect a clinically modest effect that may not apply in the general population. In addition, RCTs may not detect chronic toxicities, especially those occurring in patients with comorbidities or that only emerge following prolonged therapy.
The registry study by Yassin et al. fills this important gap in applicability of RCT results to daily clinical practice, by proving evidence for both effectiveness and safety, as well as highlighting marked benefits on new lipid outcomes that are now being endorsed by major dyslipidemia guidelines.