This is the first study to show that testosterone therapy can completely prevent progression of prediabetes, which is present in half of men with hypogonadism, to type 2 diabetes. In contrast, 40.2% of untreated hypogonadal men with prediabetes developed type 2 diabetes. The National Diabetes Education Program (NDEP) Guiding Principles for the Care of People with or at Risk for Diabetes has stated that the critical therapeutic goal in patients with prediabetes is prevention of progression to type 2 diabetes.31 The present study shows that testosterone therapy fulfills this criterion.
Interventions that aim to prevent prediabetes progression to diabetes should ideally restore normoglycemia rather than just maintain the prediabetic state. In this regard, it is particularly notable that 90% of testosterone-treated men achieved regression to normal glucose regulation with HbA1c <5.7% (39 mmol/mol), and hence resolution of prediabetes.
It is important to point out that not a single patient in the testosterone group developed type 2 diabetes. In the control group of untreated patients with hypogonadism and prediabetes there was severe deterioration of fasting glucose, triglycerides and cholesterol over time, despite the fact that they had better metabolic status at baseline than patients in the testosterone group. This is in agreement with previous studies demonstrating that the onset of the diabetogenic process starts 10 to 20 years prior to the diagnosis of frank type 2 diabetes.33,34 Heianza et al.,35 showed that in 1,722 non-diabetic individuals aged 26-80 years, fasting glucose and HbA1c were elevated 10 years prior to type 2 diabetes diagnosis. Furthermore, in the Whitehall study, comprising 6,538 subjects (71% male, 91% white) without type 2 diabetes at baseline, subjects who developed type 2 diabetes had higher fasting glucose levels 13 years before their diagnosis. The largest study with the longest follow-up of type 2 diabetes development during the prediabetic period showed that metabolic deterioration starts 2 decades prior to the diagnosis of type 2 diabetes.34
Emerging data suggest that long-term testosterone therapy for up to 12 years also can result in remission of type 2 diabetes18. HbA1c of patients who went into remission dropped from 8.3% (67 mmol/mol) at baseline to 5.7% (39 mmol/mol) at the last measurement18. This was accompanied by reductions in fasting glucose from 7.8 mmol/L to 5.4 mmol/L, fasting insulin from 24.7 to 7.6 µU/mL and HOMA-IR from 8.7 to 1.8. Body weight declined progressively from 107 to 89 kg (17% weight loss) and waist circumference from 108 to 97 cm.18
In the present study, long-term testosterone therapy with injectable testosterone undecanoate for up to 8 years resulted in normalization of testosterone levels and improvement in symptoms of hypogonadism, assessed by AMS scores. This was accompanied by a sustained and clinically meaningful weight loss of nearly 9%. Notably, this large amount of weight loss was progressive and sustained over the entire treatment period of 8 years (Figure 2). A previous study showed that over 90% of men with hypogonadism are overweight or obese, and almost all of these patients achieved a weight loss of more than 10% after long-term testosterone therapy for up to 8 years32. Weight loss in response to testosterone therapy may be one of the main contributors to the prevention of prediabetes progression to diabetes reported in the present study, and resolution of type 2 diabetes.29 A weight loss of 10% is notoriously difficult to achieve, and even harder to maintain long-term, through diet and exercise interventions.36,37 Clinical trials assessing efficacy of lifestyle interventions, as well as pharmacotherapy for obesity, are characterized by high attrition rates.38 In the present study there was no treatment-related attrition; 2 men in the testosterone group dropped out and this was due to relocation.
The main mechanism explaining how testosterone therapy prevents development of diabetes is likely improvement in insulin sensitivity.9,39 In a randomized controlled trial it was shown that testosterone therapy for 24 weeks in men with hypogonadism, obesity, and type 2 diabetes increased insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lean mass (+3.4 kg), while reducing body fat (-3.3 kg)16. At the cellular level, testosterone therapy increases the expression of the glucose carrier Glut 4, the insulin receptor and the insulin receptor substrate (IRS-1), providing an enhanced capacity for insulin-mediated glucose transport16. Accordingly, in the present study there were significant reductions in three lipid parameters that are surrogate measures of insulin resistance; the triglyceride:HDL ratio,40 TyG index,41 and LAP.42
Another contributing factor to the prevention of prediabetes progression to diabetes is the consistent increase in lean body (muscle) mass with testosterone therapy.43 Several studies show that a larger muscle mass is associated with higher insulin sensitivity, lower HbA1c and reduced risk for prediabetes and overt type 2 diabetes, in both older and younger people.44,45 After adjusting for age, ethnicity, sex, obesity and waist circumference, each 10% increase in muscle mass index (calculated as muscle mass divided by height squared) is associated with a 14% reduction in insulin resistance and a 23% reduction in prediabetes risk.44 And vice versa, a lower muscle mass is associated with higher fasting and postprandial blood glucose levels, as well as elevated insulin levels.44 We do not have body composition data for our subjects; however, a meta-analysis of randomized controlled trials shows that testosterone therapy results in significant reductions in fat mass and increases in lean (muscle) mass, as well as reductions in fasting glycemia and insulin resistance43.
The present study confirms that long-term testosterone therapy significantly improves the lipid profile (figure).23 A similar lipid profile improvement was seen in a previous study of testosterone therapy for up to 10 years in men with hypogonadism and obesity.23 The improvements seen in non-HDL and remnant cholesterol are particularly notable. Non-HDL-C better reflects the increased cardiovascular risk associated with high apoB levels and small LDL particle size, which are hallmarks of obesity.46 When triglyceride levels exceeds 150 mg/dL – as is commonly seen in patients with obesity, the metabolic syndrome and diabetes - LDL particle number, apoB and VLDL levels increase without concomitant elevations in LDL-C.46-48 Thus, non-HDL-C is more reflective of atherogenicity in persons with elevated triglycerides.49 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.49 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.50 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.51 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.51
Another result from the present 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.52 Population-wide studies have demonstrated that elevated triglyceride-rich lipoproteins are causally associated with atherosclerotic cardiovascular disease, whereas low HDL cholesterol is not.53,54 The causal risk increase for a 1-mmol/L (39 mg/dL) increase of non-fasting remnant cholesterol was 2.8-fold.53 Notably, in the present study, while the testosterone treated group experienced a reduction in remnant cholesterol of 0.7 mmol/L, the untreated group had an increase of 1.3 mmol/L. This amounts to approximately a 3-fold increase risk of cardiovascular disease in men with hypogonadism who do not receive testosterone therapy.53 It is imperative that this highly increased risk of cardiovascular disease, coupled with the marked deterioration in other metabolic risk factors leading to development of type 2 diabetes, is communicated to patients who are unsure of whether to start testosterone therapy. It can be expected that this knowledge will help patients stay motivated to adhere to testosterone therapy long-term.
It is reasonable to hypothesize that these improvements in dyslipidemia contribute to the reduction in myocardial infarction and cardiovascular mortality found in the present study, as well as in a previous study of long-term testosterone therapy.55 It is remarkable that mortality was over 2-fold higher in the untreated group, and more non-fatal myocardial infarctions occurred in the untreated group (5 out of 87) than the testosterone group (2 out of 229) in the present study. Significant reductions in mortality after long-term testosterone therapy in men with hypogonadism and type 2 diabetes have also been found in other studies.56,57
In summary, given the observed improvements in glycemia, body weight, waist circumference and lipids, the present study shows that long-term testosterone therapy provides a multifactorial and comprehensive risk reduction of diabetes and cardiovascular disease in men with hypogonadism and prediabetes. Resolution of prediabetes and achievement of nearly 10% weight loss that is maintained long-term, coupled with excellent adherence, positions testosterone therapy as a very promising treatment of a rapidly growing population of men at high risk for type 2 diabetes and cardiovascular disease.