The use of testosterone replacement therapy for the treatment of adult males with type 2 diabetes and hypogonadism: a meta-analysis of randomised controlled trials

Despite varying findings, TST has been used for a long time to treat hypogonadal males with type 2 diabetes mellitus (T2DM). The function of TST was evaluated in this meta-analysis in hypogonadal males with type 2 diabetes. Relevant randomised controlled trials and observational studies were identified by searching PubMed, Embase, and Google Scholar. The effects of TST were evaluated using pooled mean differences (MDs) and relative risks with 95% confidence intervals (CIs).Our meta-analysis includes 3,002 hypogonadal, type 2 diabetics from 13 randomised controlled trials and 2 observational studies. Total testosterone levels increase significantly with testosterone replacement, and TST significantly improves glycemic management compared to placebo by lowering homeostatic model assessment of insulin resistance (WMD = -1.47 [-3.14, 0.19]; p=0.08; I2=56.3%), fasting glucose (WMD = -0.30 [-0.75, 0.15]; p=0.19; I2= 84.4%), fasting insulin (WMD = -2.95 [-8. Overall, TST resulted in a greater increase in free testosterone levels compared to placebo (WMD = 81.21 [23.87, 138.54] p=0.07; I2= 70%) when comparing patients' individual measurements.We conclude that TST can help hypogonadal Type 2 Diabetes patients with better glycemic control and hormone levels, as well as lower total cholesterol, triglyceride, and LDL cholesterol while raising HDL cholesterol. Therefore, in addition to the usual care for diabetes, we advise TST for these individuals.Introduction:An abnormality in one or more of the testicular hormone concentrations along the hypothalamic-pituitary-testicular axis is the cause of the clinical syndrome known as hypogonadism. In men, hypogonadism is diagnosed when low levels of testosterone (both total and free) are found in the blood. [1] The annual incidence rate of hypogonadism is 12.3 per 1000 people, affecting between 5.1% and 12.3% of men between the ages of 30 and 79. When free testosterone levels fall below 225 pmol/l (65 pg/ml), a pathology is present and treatment is necessary. [2] Due to the devastating effects it can have on a patient's ability to perform basic bodily functions and their overall quality of life, hypogonadism is a global health problem. Recent studies have found strong evidence connecting hypogonadism and type 2 diabetes mellitus (T2DM). This is because low T levels cause an increase in fat storage, insulin resistance, and poor glycemic control, and a higher risk of obesity increases the likelihood of TD. [3] The use of testosterone in routine clinical care for type 2 diabetes is being questioned by a growing (and sometimes conflicting) body of research. Numerous studies have shown that testosterone treatment lowers the risk factors for cardiovascular disease and diabetes in men with type 2 diabetes, including systolic and diastolic blood pressure, lipid profiles, insulin sensitivity, inflammation, and levels of fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c). It has also been suggested that men with hypogonadism who undergo long-term testosterone therapy have a lower chance of developing type 2 diabetes and a higher quality of life, as measured by the Aging Male Symptoms (AMS) questionnaire. [5] There were, however, studies that found the opposite. Hypogonadal patients with type 2 diabetes have been shown in multiple studies to benefit greatly from testosterone replacement therapy (TRT), as measured by decreases in fasting serum glucose (FSG), fasting serum insulin (FSI), and haemoglobin A1C (HBA1C). [6] These indicators did not significantly decrease in TRT groups, according to other data. Total cholesterol, triglyceride, and serum low-density lipoprotein (LDL) levels have all been shown to be reduced in studies where TRT was used, while high-density lipoprotein (HDL) levels were found to be increased. [7,8] But no other studies found evidence of a statistically significant improvement in lipid metabolism.Only a small number of randomised control trials and observational studies have looked at the role of TRT in male hypogonadism caused by TDM, and the results have been inconsistent. To better understand the role of TRT in hypogonadal males with type 2 diabetes, we conducted a systematic review and meta-analysis. As far as we can tell, this meta-analysis provides the most recent look at how testosterone therapy stacks up against no treatment or placebo.Methods and MaterialsThis meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). [9]Search strategyMethods From the study's inception on September 5, 2022, to the present day, PubMed (Medline) and Cochrane were combed extensively. Searches on ClinicalTrials.gov, Google Scholar, and Medrxiv uncovered the grey literature and preprints. An indexing strategy was developed using both keywords and Medical Subject Headings (MESH terms). ['Testosterone' OR 'TST' OR Testosterone undecanoate] were among these. AND [[Diabetes Mellitus OR [Hypogonadism]]. Table S1 provides details on the search parameters and parameters. In conducting this search, we did not apply any filters or limitations. In the case of non-English text, Google Translate was used to produce an English version. The studies were located through manual searches of review articles. Two reviewers independently and anonymously evaluated the titles, abstracts, and full texts (MK and SK). The relevant studies were imported into Endnote X9 to avoid repetition (Clarivate Analytics, US).Criteria for EligibilityCriteria for inclusionThe studies were chosen based on their language, study design, patient population, intervention, comparison, outcomes of interest, and definition.Publications were limited to those written in English, and studies had to be either randomised clinical trials or observational studies that met certain criteria for inclusion before the meta-analysis could be performed.Hypogonadism patients are those who have type 2 diabetes and have been diagnosed with the condition.Patients who participated in the study's exposure group included those who had received testosterone therapy.The non-TST group served as a control and received either the gold standard of care or a placebo in this analysis.Implications on glucose homeostasis and hormonal levels after treatment constitute the Primary Outcomes.Measurements of cholesterol, body mass index, waist size, fat percentage, and systolic and diastolic blood pressure were recorded as secondary outcomes.Criteria for exclusionThe following significant exclusion criteria were established to ensure the quality of this meta-analysis:• There are no agreed-upon criteria for making a diagnosis of late-onset hypogonadism or type 2 diabetes, determining the appropriate population to study, dosage, or administration method for testosterone, or evaluating outcomes.There are no control or placebo groups• Duplicate publications • Inadequate data for estimating a mean difference (MD) with a 95% confidence intervalIn addition, the 25-item CONSORT checklists, which stress describing how trials were conceived, analysed, and interpreted, were used to assess all included RCTs (Table S2). The 25 reported items were used to evaluate the quality of the included RCTs. The strength of a randomised controlled trial (RCT) correlates with the number of outcomes that were reported. All 25 criteria should be present in high-quality research.Data ExtractionData ExtractionTwo researchers (HN and RI) independently read and evaluated each article to determine whether or not it should be included in the review. Questions were answered and doubts dispelled. We collected the following data from each trial: first author's name, publication year, country, ethnicity, testosterone cut-off point, diabetes duration, testosterone regimen, medications on comparators, mean age, Hba1c percentage, and total serum testosterone level. Table 1 summarises these facts. Parameters such as HOMA-IR, fasting plasma glucose, fasting serum insulin, haemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, body fat percentage, body mass index, systolic blood pressure, diastolic blood pressure, erectile function, and the ageing male score are listed in Table 2.Study quality assessmentPublished RCT quality was evaluated using a modified version of the Cochrane Collaboration risk of bias tool [10], while observational study quality was measured using the New Castle Ottawa scale. [11] Statistical analysis The aforementioned meta-analysis was conducted using the statistics software Review Manager 5.4 (Cochrane Collaboration). For a simple yes/no outcome, we found the relative risk (RR) and 95% CI. The average and standard deviation were used to illustrate continuous results. In this meta-analysis, we show the combined effect of relative risks (RRs) and weighted mean differences (WMDs) calculated with the generic-inverse variance and continuous outcome functions using a random-effects model. Results were considered to be statistically significant when the p-value was less than 0.05. In order to assess the possibility of publication bias, funnel plots were constructed for primary outcomes.Using I2 statistics, we were able to quantify the degree of disagreement between studies. Low heterogeneity was represented by an I2 value of 25%, moderate heterogeneity by a value between 25% and 50%, and high heterogeneity by a value of 50% or more. A sensitivity analysis on outcomes with a high degree of heterogeneity was performed to investigate the impact of individual studies on the overall pooled estimate.ResultsStudy selectionThe initial literature search yielded a total of 659 articles. Out of the initial 30 publications, only 15 met the inclusion criteria for this meta-analysis; 2 were observational [12,24] and 13 were randomised trials [5,8,13-23]. The distinguishing characteristics of the selected studies are outlined in (Supplementary table S2 and S3)Baseline characteristics Three thousand and two people met the criteria for hypogonadism across the 15 studies; 1484 received testosterone and 1518 received a placebo. Six studies [8,12,14,18,20,24] required the presence of at least three sexual symptoms and a total testosterone level of 12 nmol/L to diagnose hypogonadism, while the remaining studies [5,13,15,16,17,19,21,22] required the presence of a total testosterone level of 15 nmol/L or a free testosterone level of 225 pmol/L to make the diagnosis. The cutoff for hypogonadism in another study [13] was set at TT13 nmol/L. The primary testosterone regimens used in the included studies varied widely. Only one study () used oral testosterone, three (15,17,21) injected testosterone gel subcutaneously, and eleven (5,8,12-14,16,18-20,22,23,24) injected testosterone intramuscularly. Testosterone was administered in a wide variety of doses and at different intervals in these studies. Only two of the RCTs [17,19] lacked a control group entirely, while the other eleven [5,8,13-16,18,20-23] were double-blind placebo-controlled studies. Table 1 and Table 2 provide information about the participants' demographics, medical histories, hormone levels, and glycemic indices as appropriate for the study.Quality assessment and publication biasAccording to the New Castle-Ottawa scale, an instrument for assessing the quality of studies, there is a low risk of bias in observational studies (Supplementary Table 4). The Cochrane method for evaluating randomised controlled trials yielded results of moderate to high quality (Supplementary Table 5). Publication bias did not affect the findings, as demonstrated by the funnel plots (Supplementary Figure S1).Primary outcomes:The effects of testosterone on glucometabolism were assessed by measuring HOMA-IR, haemoglobin A1c, fasting serum glucose (FSG), and fasting serum insulin (FSI). Data from 9 of the 15 studies reporting on HOMA-IR ([5,8,13,14,16,17,21,22,24]) showed that testosterone therapy was superior to placebo at lowering HOMA-IR levels (WMD = -1.47 [-3.14, 0.19]; p = 0.08; I2 = 56.3%). Patients in the testosterone group showed a greater decrease in FSG after treatment compared to those in the placebo group (WMD = -0.30 [-0.75, 0.15]; p=0.19; I2= 84.4%). FSG was measured in 14 [5,8,12-19,21-24] of the 15 studies. WMD = -2.95 [-8.64,2.74]; p = 0.31; I2 = 49.3%]; 8 [8,13,15-18,22,24] of 15 studies found that patients treated with testosterone had greater reductions in FSI levels. Among the 15 studies, 13 reported HbA1c values, and pooled analysis showed that testosterone treatment was associated with a greater improvement in post-treatment HbA1c levels (WMD = -0.29 [-0.57, -0.02] p=0.04; I2= 89.8%). (Figure 3)Total testosterone, free testosterone, serum hormone binding protein (SHBG), and prostate specific antigen (PSA) were taken into account to determine testosterone's impact on hormone levels. The pooled analysis of 9 studies that measured total testosterone levels [5,12,13,18,19,21-24] found that testosterone therapy is associated with a significant increase in total testosterone levels (WMD = 4.51 [2.40, 6.61] p0.0001; I2= 96.3%). The in-study heterogeneity was unaffected by excluding individual studies from the pooled analysis.Combining data from three studies [13,14,21] found that patients on testosterone therapy experienced a greater increase in free testosterone levels compared to those on placebo (WMD = 81.21 [23.87, 138.54] p=0.07; I2= 70%). After pooling data from 5 studies [13,17,21,22,23], researchers found that SHBG level decreased more with testosterone therapy (WMD = -1.28 [-5.51, 2.96] p=0.55; I2 = 0%). There was no statistically significant difference in PSA levels between the two groups after therapy (WMD = -0.02 [-0.13, 0.08] p=0.65; I2 = 0%) across seven studies [8,13,14,15,17,21,23].Secondary outcomes: (Table 3)Treatment with testosterone has been shown in a pooled analysis of secondary outcomes to improve HDL cholesterol and IIEF, as well as reduce total cholesterol, LDL cholesterol, triglyceride, body fat, waist circumference, body mass index, systolic blood pressure, diastolic blood pressure, arterial mean stiffness, and mortality.Discussion:Recent studies have found that hypogonadism occurs in a high percentage of men with Type-2 diabetes. Despite growing knowledge of the correlation between T2D and hypogonadism, no universally accepted guidelines exist for dealing with the condition. The purpose of this meta-analysis was to develop clear, evidence-based recommendations for the treatment of hypogonadism in men with Type 2 diabetes mellitus who are taking testosterone replacement therapy. Evidence linking type 2 diabetes and low blood testosterone due to an insulin has been established by multiple studies a significant incidence of hypogonadism in males with diabetes is more in males with diabetes than in men across the including in the and The effects of testosterone replacement therapy in hypogonadal males with type 2 diabetes were compared to those in a control group in a systematic review and meta-analysis 15 studies and patients (T2DM). All men with Type 2 diabetes and all men with a body mass greater than 30 or a waist greater than were for for hypogonadism by the of in The guidelines to testosterone the high of hypogonadism in type 2 diabetes. for hypogonadism was for in by the of in all men with Type 2 diabetes and in all men with a body mass of 30 or or a waist of or more. In of the high of hypogonadism in such as type 2 diabetes, the guidelines for the In men with hypogonadism, testosterone replacement therapy has been shown to have a effect on a wide of including sexual and function, body quality of life, and cardiovascular the for testosterone are up for effects of testosterone replacement therapy have been by the guidelines into two those with a strong to testosterone such as and an increase in decreased and the of and those with a such as and the of results the of studies [5,8,12-19,21-24] that TRT can significantly glucose control by for fasting serum glucose (FSG), fasting insulin (FSI), and glycated haemoglobin (HBA1C). Recent has established a correlation between HOMA-IR and body mass index, waist circumference, and sensitivity, as measured by in HOMA-IR, and blood and levels, was also by testosterone the presence of Testosterone replacement therapy for hypogonadal males with diabetes has been to in both body mass and glucose The testosterone treatment group showed statistically significant in body mass index, fasting glucose, blood pressure, lipid profiles, and according to a of testosterone treatment to concentrations for decreased insulin resistance HOMA-IR p = had no effect on body or waist in a testosterone trial men the of were and had diabetes at Testosterone therapy has been to long-term a decrease in risk and in the of diabetes, according to a number of case studies. with testosterone was for a with erectile and at intervals following a Patients on testosterone therapy in fasting blood glucose after to below after 12 and below this insulin resistance at and serum lipid levels and To understand the between and glucose more studies are meta-analysis, we looked at a lipid of total cholesterol, high-density lipoprotein low-density lipoprotein and levels. studies found that testosterone had lower total cholesterol levels compared to placebo the other 14 studies showed that while HDL cholesterol levels there was less of a difference in LDL cholesterol levels between the two meta-analysis found that TRT significantly total cholesterol compared to placebo. There was also a in triglycerides, it was not statistically HDL levels after TRT compared to the placebo role in HDL was due to a of evidence and results. It has been shown that high doses of TRT lower levels of HDL and lipoprotein effect on blood lipid and lipoprotein levels is The 14 studies that up meta-analysis all showed a in diastolic blood pressure and a in systolic blood pressure The effects of testosterone on lipid in the blood are In men with and type 2 diabetes, low testosterone has been to levels of LDL and and decreased In patients with high testosterone profiles, studies found no between serum lipid levels or TRT has been shown to significantly reduce and total cholesterol in men with and hypogonadism in systematic and of the patient's waist and body mass can be used for for Testosterone is as an due to ability to decrease and increase mass in males with hypogonadism. studies, which the aforementioned randomised controlled have found that testosterone therapy results in a greater in body mass significant correlation between total serum testosterone and and was found in three studies. with testosterone significantly reduced while in sexual as measured by the scale, the erectile and the scale, have been associated with low testosterone in men nmol/L function, and not significantly however, according to the the was the only of data on we can that the improvement in quality of was to a in sexual levels of testosterone were including and total and free testosterone levels while SHBG PSA levels were not to this therapy. 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