Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes
Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men with Hypogonadism Prevents Progression from Prediabetes to Type 2 Diabetes: Eight-Year Data from a Registry Study. Diabetes Care 42(6): 1104-1111 (2019)
Overweight and obesity affects 82% of the male population in Western countries.1 The prevalence of “overfat” - defined as excess adiposity measured accurately (directly, such as by DXA, or indirectly, such as by waist-to-height ratio) combined with at least one additional cardiometabolic risk factor - is even more alarming at 91%.2 The mean age-adjusted waist size in men in Western countries is 101 cm, while the prevalence of abdominal obesity – defined as waist circumference 102 cm or higher – is 44%.3 In turn, among men with abdominal obesity, 86% have at least one other cardiometabolic risk factor.4
These statistics suggest that nearly every man who visits a physician has borderline or frank abdominal obesity, with accompanying metabolic risk factors such as prediabetes, defined as elevated HbA1c levels in the range of 5.7-6.4%. Considering that the lifetime risk of progression from prediabetes to type 2 diabetes is as high as 74%,5 and that diabetes is one of the most expensive diseases imposing a cost to the healthcare system in the range of 710 – 1160 billion Euro annually,6 diabetes prevention is critically urgent.
Many previous studies, both randomized controlled trials and long-term “real-life” registry studies, have shown that testosterone therapy significantly improves insulin sensitivity (HOMA-IR),7-15 insulin levels7,8,13,16 and HbA1c.7,10−12,14,15,17−23 This suggest that there may be a chance to prevent type 2 diabetes with testosterone therapy.
Here we present the results of a new important study, published in the authoritative journal Diabetes Care, that investigated if long-term testosterone therapy in men with hypogonadism and prediabetes can prevent the progression to frank type 2 diabetes.24
What is known about testosterone, prediabetes and type 2 diabetes
Considering the high prevalence of hypogonadism in men with type 2 diabetes, in 2018 the American Diabetes Association (ADA) added to their Standards of Medical Care in Diabetes the recommendation to measure serum testosterone in men with diabetes and signs and symptoms of hypogonadism.25 A growing number of studies are showing that the prevalence of hypogonadism is also higher in men with milder forms of dysglycemia, such as impaired fasting glucose and/or impaired glucose tolerance, even after adjusting for age and BMI.5,26-28 For example, men with prediabetes are nearly twice as likely to have low testosterone levels compared to men with normoglycemia, regardless of age, and even after adjusting for BMI, waist circumference, individual metabolic syndrome components, and the metabolic syndrome as an entity.28
The lifetime risk of progression from prediabetes to diabetes is as high as 74%.5 The key to type 2 diabetes prevention is weight loss.29 The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) comprehensive clinical practice guidelines for medical care of patients with obesity strongly recommend that male patients with overweight, obesity, metabolic syndrome or prediabetes should aim for a weight-loss goal of 10% to prevent progression to diabetes.30 The Guiding Principles for the Care of People with or at Risk for Diabetes, published by NDEP (National Diabetes Education Program), also endorse a weight loss goal of 10% to prevent diabetes.31
Since long-term testosterone therapy in men with hypogonadism results in a marked and sustained weight loss32, it is reasonable that men with hypogonadism and prediabetes - defined as HbA1c 5.7-6.4% (39-46 mmol/mol) according to the American Diabetes Association - would experience a reduced or slower progression to type 2 diabetes with testosterone therapy. The present study aimed to examine whether long-term testosterone therapy can halt or prevent progression of prediabetes to overt type 2 diabetes in men with hypogonadism.
What this study adds
316 men with prediabetes (defined as HbA1c 5.7–6.4%) and hypogonadism, defined as total testosterone levels ≤12.1 nmol/L combined with symptoms, were included in the study. 229 men received testosterone undecanoate injections (testosterone group), and 87 men served as untreated control subjects (untreated group). Metabolic and anthropometric parameters were measured twice yearly for 8 years.
At baseline, both groups had the same BMI, HbA1c and International Index of Erectile Function, Erectile Function Domain (IIEF-EF) of 30 kg/m2, 5.9% and 11, respectively. Total testosterone level was 8.2 nmol/L in the testosterone group and 9.6 nmol/L in the untreated group. The prevalence of prediabetes was 51%. Men in the testosterone group had a worse metabolic profile at baseline, which was accounted for in the statistical analysis of the results.
Testosterone therapy increased testosterone levels by 8.5 nmol/L, while in the untreated group it was reduced by 0.9 nmol/L. At the end of the study, testosterone levels were 16.7 and 8.5 nmol/L (482 and 245 ng/dL) in the testosterone group and untreated group, respectively.
Testosterone treatment led to substantial improvements in glycemic parameters, with significant reductions in fasting blood glucose and HbA1c. In contrast, in the untreated group glycemic parameters worsened over time. At the last observation, all 229 patients (100%) in the testosterone group had an HbA1c of <6.5% (48 mmol/mol), and 205 of these 229 patients (90%) achieved normal glucose regulation with an HbA1c <5.7% (39 mmol/mol). In the untreated group, only 1 patient (of 87, i.e. 1%) had HbA1c <5.7% (39 mmol/mol) whereas 35 men (40.2%) had progressed to frank type 2 diabetes with HbA1c >6.5% (48 mmol/mol).
At baseline, in the entire cohort the prevalence of obesity, overweight and normal weight was 51%, 43% and 6%, respectively. The testosterone treated patients achieved a weight loss of 8% at 8 years, while the untreated patients experienced a weight gain of 9%. This corresponded to a weight loss of 9.2 kg in testosterone treated patients and a weight gain of 8 kg in the untreated group, with corresponding changes in BMI. Waist circumference decreased by 6.8 cm in the testosterone group and increased by 7.4 cm in the untreated group, with corresponding changes in the waist:height ratio.
Testosterone treatment significantly reduced levels of total cholesterol, LDL, non-HDL, remnant cholesterol and triglycerides, as well as the triglyceride:HDL ratio, triglyceride-glucose index (TyG index, calculated as fasting triglycerides [mg/dL] x fasting plasma glucose [mg/dL]) / 2) and lipid accumulation product (LAP, calculated as (waist circumference (cm) - 65) x triglycerides (mmol/L)), while increasing HDL (figure 1).
In testosterone treated patients there was a clinically significant reduction in AMS scores, which reflects improvements in symptoms of hypogonadism. In untreated patients AMS remained unchanged for the first 2-3 years of follow-up and then gradually worsened over the remaining years of the study.
Testosterone treatment led to predictable increases in hemoglobin and hematocrit that stayed within the normal range during the entire 8-year long observation period.
Mortality was over 2-fold higher in the untreated group: 7.4% in the testosterone group and 16.1% in the untreated group. One patient (0.4%) in the testosterone group and 5 patients (5.7%) in the untreated group had a non-fatal myocardial infarction (MI). No patient in the testosterone group and 1 patient (1.1%) in the untreated group had a non-fatal stroke (figure 2).
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.