Diabetes Ther (2018) 9:1061–1072 https://doi.org/10.1007/s13300-018-0415-3 ORIGINAL RESEARCH Is a Previously or Currently Reduced Testosterone Level in Male Patients with Type 2 Diabetes Mellitus a Risk Factor for the Development of Coronary Artery Disease? A Systematic Review and Meta-analysis Feng Huang Received: February 23, 2018 / Published online: April 4, 2018 The Author(s) 2018 ratio (RR) with the 95% conﬁdence interval ABSTRACT (CI), as obtained using the RevMan 5.3 software. Results: 3467 male patients with T2DM (1079 Introduction: We aimed to systematically patients with a low testosterone level versus investigate the association between testosterone 2388 patients with a normal testosterone level) level and cardiovascular risk in male patients were included. The results of this analysis with type 2 diabetes mellitus (T2DM) by com- showed that when a random effects model was paring male T2DM patients with low testos- used, a higher risk of CAD/cardiovascular dis- terone levels to male T2DM patients with ease was observed in diabetic patients with a normal testosterone levels at baseline in terms low testosterone level than in those with a of the number of cases of coronary artery dis- normal testosterone level (RR 1.24, 95% CI ease (CAD). 0.94–1.63; P = 0.13). However, the difference in Methods: Online databases were carefully sear- risk was not statistically signiﬁcant. Similarly, ched for studies relating to testosterone, dia- with a ﬁxed effects model, a low testosterone betes mellitus, and cardiovascular risk by using level was associated with a higher CAD/cardio- the search terms ‘testosterone,’ ‘diabetes melli- vascular risk of disease (RR 1.12, 95% CI tus,’ and ‘coronary artery/cardiovascular dis- 0.98–1.34; P = 0.08); in this case, the difference ease.’ The only endpoint in this analysis was in risk between the T2DM patients with low and CAD/atherosclerosis/coronary plaque/major normal testosterone levels approached statisti- adverse coronary event prior to or following cal signiﬁcance. testosterone reduction at baseline. The analyti- Conclusion: A previously or currently reduced cal parameters used in this analysis were the risk testosterone level was not found to be statisti- cally signiﬁcantly associated with a high risk of Enhanced content To view enhanced content for this CAD/cardiovascular disease in male patients article go to https://doi.org/10.6084/m9.ﬁgshare. with T2DM. However, the difference in risk between the T2DM patients with low and nor- mal testosterone levels was observed to F. Huang (&) approach statistical signiﬁcance. Institute of Cardiovascular Diseases and Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Keywords: Cardiovascular disease; Coronary Prevention, The First Afﬁliated Hospital of Guangxi artery disease; Male; Testosterone; Type 2 Medical University, Nanning, Guangxi, diabetes mellitus People’s Republic of China e-mail: firstname.lastname@example.org 1062 Diabetes Ther (2018) 9:1061–1072 • Studies reporting the number of patients INTRODUCTION with CAD at baseline or during the follow-up period Type 2 diabetes mellitus (T2DM) is a growing The exclusion criteria were as follows: threat to the health of many in their second or • Studies that did not focus on male patients third age around the world . Unfortunately, with T2DM coronary artery disease (CAD), which is • Studies that did not compare diabetic responsible for a high percentage of all deaths patients with low testosterone levels to dia- globally, is often also a long-term complication betic patients with normal testosterone of T2DM . Recently, research has shown an levels important link between a low testosterone level • Studies that did not report the number of and the development of atherosclerosis in male patients with CAD at baseline or during the patients . However, the association between a follow-up period. low testosterone level and CAD/cardiovascular risk is still being debated . Therefore, by comparing CAD rates in diabetic patients with Endpoints low and normal testosterone levels at baseline, we aimed to systematically investigate this issue The only endpoint in this analysis was CAD/ in male patients with T2DM. atherosclerosis/coronary plaque/major adverse coronary event prior to or following testos- terone reduction. METHODS Outcomes that were considered relevant in each study are recorded in Table 1. Searched Databases and Strategies Data Extraction and Review The Cochrane database of randomized con- trolled trials, PubMed/Medline, and EMBASE The PRISMA guideline was followed . The were carefully searched for studies related to studies were carefully checked and important testosterone, diabetes mellitus, and CAD/car- relevant data were extracted by the reviewer diovascular risk using the search terms ‘testos- (FH). The following data were extracted and terone,’ ‘diabetes mellitus,’ and ‘cardiovascular cross-checked again: disease.’ The term ‘cardiovascular disease’ was • Author names later interchanged with the terms ‘atheroscle- • Year of publication rosis’ and ‘coronary artery disease.’ Abbrevia- • The type of study performed (randomized tions such as T2DM, DM, CVD, and CAD were trial or observational cohort); also used to further enhance this search process. • The total numbers of patients with low and We only searched for articles published in normal testosterone levels English. • Baseline characteristics of the patients • The patient enrollment period Inclusion and Exclusion Criteria • The testosterone level ranges that were con- sidered to be low and normal During this selection process, various inclusion • The total number of patients with CAD and exclusion criteria were applied to all of the articles. The following inclusion criteria were Statistical Analysis used: • Studies including only male patients with The analytical parameters used were the risk T2DM ratio (RR) and the 95% conﬁdence interval (CI) • Studies comparing diabetic patients with low obtained using the RevMan 5.3 software. testosterone levels to diabetic patients with Heterogeneity was assessed via the Q statistic normal testosterone levels test and the I statistic test . Diabetes Ther (2018) 9:1061–1072 1063 Table 1 Cardiovascular outcomes reported in the studies of interest Study Cardiovascular outcome reported Time period Cheung et al. (2016)  Coronary heart disease At baseline Farias et al. (2014)  Coronary plaque At baseline Gianatti et al. (2016)  Cardiovascular risk At baseline Hackett et al. (2016)  Major adverse coronary events At baseline Liu et al. (2013)  Coronary artery disease At baseline Muraleedharan et al. (2013)  Pre-existing coronary vascular disease At baseline A P value of B 0.05 was assumed to indicate • Ten articles reported studies that did not involve male patients with T2DM statistical signiﬁcance. A ﬁxed effects model (I \ 50%) or a random • Four articles did not report the relevant study endpoint effects model (I [ 50%) was used depending on the value of I obtained. In this analysis, both a Finally, only six articles [7–12] were selected ﬁxed effects and a random effects were used for the present analysis (Fig. 1). during the subgroup assessment. Sensitivity analyses were also carried out by General Features of the Studies excluding each of the studies in turn and con- ducting a new analysis following each A total of 3467 male patients with T2DM (1079 exclusion. patients with a low testosterone level versus 2388 patients with a normal testosterone level) Ethics were included in this analysis (Table 2). Two randomized trials and four observational The meta-analysis reported here was based on cohorts were considered. The patient enroll- previously conducted studies and did not ment period varied between the years 2002 and include any studies with human participants or 2013. The ranges of testosterone levels along with other features of the studies included in animals performed by any of the authors. Hence, ethical approval was not required. this analysis are listed in Table 2. Baseline Characteristics of the Patients RESULTS A summary of the baseline characteristics of the Searched Results patients is shown in Table 3. Mean age ranged from 58.0 to 65.6 years. Duration of diabetes Two hundred forty-nine (249) articles were mellitus ranged from 6 to 10.5 years. In addi- obtained during the database search. After two tion, during a two-month control phase, gly- reviewers had carefully reviewed the abstracts, cosylated hemoglobin ranged between 6.80% 228 publications were excluded since they were and 7.90%. In terms of the baseline character- either not directly related to the present istics of the patients, there was almost no dif- research or they were duplicates. Twenty-one ference between the diabetic patients with low (21) full-text articles were assessed for eligibility. testosterone and those with normal testos- Further articles were eliminated for the follow- terone levels. ing reasons: • One article was a review article 1064 Diabetes Ther (2018) 9:1061–1072 Fig. 1 Flow diagram representing the study selection process Association of a Low Testosterone Level CI 0.98–1.34; P = 0.08; Fig. 3). In this case, even with Cardiovascular Risk though the difference in CAD/cardiovascular disease risk between the low and normal testosterone T2DM patients was again not sta- The results of this analysis showed that when a tistically signiﬁcant, it did approach random effects model was used, diabetic signiﬁcance. patients with a low testosterone level were at a Sensitivity analysis was also carried out in relatively high risk of CAD/cardiovascular dis- order to conﬁrm that the results of this analysis ease (RR 1.24, 95% CI 0.94–1.63; P = 0.13; were not strongly inﬂuenced by the results from Fig. 2). However, the difference in CAD/cardio- one of the studies in particular (Fig. 4). vascular disease risk between the low and nor- The sensitivity analysis showed that the mal testosterone T2DM patients was not results of the analysis did not change signiﬁ- statistically signiﬁcant. cantly when any one of the following studies Similarly, when a ﬁxed effects model was was excluded from the analysis: Cheung et al. used, diabetic patients with a low testosterone  (RR 1.15, 95% CI 0.88–1.52; P = 0.31), Farias level again were at a higher risk of CAD/car- et al.  (RR 1.17, 95% CI 0.85–1.61; P = 0.33), diovascular disease than the diabetic patients Gianatti et al.  (RR 1.18, 95% CI 0.90–1.55; with a normal testosterone level (RR 1.12, 95% Diabetes Ther (2018) 9:1061–1072 1065 Table 2 General features of the studies considered Study Type of study Patient No. of No. of Low and normal/high enrollment patients patients with TT ranges period with low normal/high (years) TT (n) TT (n) Cheung et al. (2016)  Observational 2008–2011 152 1087 \9 and C 9 nmol/L Farias et al. (2014)  Observational 2010–2012 35 78 \12.1 and C 12.1 nmol/L Gianatti et al. (2016)  RCT 2009–2013 43 43 Exogenous Hackett et al. (2016)  RCT 2007–2009 362 320 B 12 and [ 12 nmol/L Liu et al. (2013)  Observational 2008 249 517 \300 and C 300 ng/dL Muraleedharan et al. (2013) Observational 2002–2005 238 343 B 10.4 and [ 10.4 nmol/L  TT testosterone, RCT randomized controlled trial Table 3 Baseline characteristics of the patients in each study a b Study Age Disease duration HBA1c LDL TC Testosterone level (years) (years) (%) LT/NT LT/NT LT/NT LT/ LT/NT NT Cheung et al. (2016)  60.4/58.4 10.0/10.0 7.90/7.70 2.43/ 4.48/ \9vs C 9 nmol/L 2.60 4.55 Farias et al. (2014)  59.0/58.0 7.90/6.00 7.05/6.90 127/ – \ 12.1 118 vs C 12.1 nmol/L Gianatti et al. (2016)  62.0/62.0 7.00/9.00 6.80/7.10 2.30/ 4.20/ 10.6 vs 11.0 nmol/L 2.20 4.50 Hackett et al. (2016)  65.5/64.2 – 7.50/7.30 – 4.10/ B 12.0 4.10 vs [ 12.0 nmol/L Liu et al. (2013)  65.6/60.5 10.50/10.30 7.40/7.30 86.7/ 154/ 240 vs 420 ng/dL 92.3 160.1 Muraleedharan et al. (2013) 60.3/58.9 – 7.50/7.20 – – 7.5 vs 15.7 nmol/L  LT low testosterone, NT normal testosterone, LDL low-density lipoprotein, TC total cholesterol, vs versus Reported in mmol or mg/dL P = 0.23), Hackett et al.  (RR 1.31, 95% CI However, when the study by Liu et al.  was 0.97–1.78; P = 0.08), and Muraleedharan et al. excluded, T2DM patients with a low testos-  (RR 1.30, 95% CI 0.88–1.93; P = 0.19). terone level were found to be at a signiﬁcantly 1066 Diabetes Ther (2018) 9:1061–1072 Fig. 2 Association of a low testosterone level with cardiovascular risk (using the random effects model) Fig. 3 Association of a low testosterone level with cardiovascular risk (using the ﬁxed effects model) higher risk of cardiovascular disease than those improves erectile function. It is also important with a normal testosterone level (RR 1.35, 95% for maintaining healthy vascular function CI 1.02–1.78; P = 0.04). throughout the body  and has other important functions which will not be dis- cussed here . A few studies have even shown DISCUSSION testosterone to be modestly cardioprotective; possible mechanisms for this cardioprotective Through this analysis, we aimed to show whe- action have been proposed  and are listed in ther a decreased testosterone level was associ- Table 4. ated with a higher risk of CAD/cardiovascular In brief, a high testosterone concentration disease in male patients with T2DM. Our results may have anti-arrhythmic properties . suggested that such a link was present, Testosterone might also decrease the QTc although, due to a lack of statistical signiﬁ- interval length, thus exerting a beneﬁcial car- cance, there was not enough evidence to prove diovascular effect. This hormone may also this link. reduce the size of an infarction in the cardiac Testosterone, which is derived from choles- muscle, further showing that it is cardioprotec- terol, is the male sex hormone . In the body, tive. Studies have also shown that testosterone most testosterone is bound to protein (about causes blood vessel vasodilation, which again 98%), while some is present as free molecules has a positive effect on the cardiovascular sys- (about 2%). The free testosterone is readily tem. Further, testosterone has been found to available in the blood and is responsible for prevent plaque formation, thus protecting from several major important functions in the male atherosclerosis . body. It is primarily synthesized in Leydig cells The association of a low testosterone level in the testes of the male sex organ . In men, with CAD/cardiovascular disease is still contro- testosterone is responsible for secondary sexual versial . However, in support of the results of features, it increases libido (sex drive), and it Diabetes Ther (2018) 9:1061–1072 1067 Fig. 4 Results of a sensitivity analysis performed using the exclusion method 1068 Diabetes Ther (2018) 9:1061–1072 Table 4 Main mechanisms that link testosterone level to the risk of coronary artery disease Testosterone... 1. Acts as an anti-arrhythmic agent, so it is cardioprotective 2. Reduces the size of a MI, so it is cardioprotective 3. Causes vasodilation of coronary vessels, so it is cardioprotective 4. May decrease QTc interval in the electrocardiogram 5. Prevents plaque formation, thus protecting from atherosclerosis 6. Reduces visceral fat accumulation and improves fasting glucose levels 7. May, according to some controversial reports, lead to blood vessel constriction at high doses, and may also increase inﬂammation, which could aggravate MI CAD coronary artery disease, MI myocardial infarction the present analysis, a Japanese study showed a waist circumference, neuropathy, and other direct link between testosterone deﬁciency and unwanted conditions . Nevertheless, a letter cardiovascular events . The authors con- of correspondence to Herna ´ ndez-Mijares et al. cluded that a low testosterone level was associ- revealed that the use of oral hypoglycemic ated with cardiovascular events in middle-aged agents and other confounding factors may have Japanese men, independent of coronary risk contributed to the fact that no association was factors and endothelial function. In addition, a observed between cardiovascular risk and a low 13-year follow-up of former multiple risk factor testosterone level in his patients with T2DM intervention trial participants showed that a . decreased endogenous testosterone level in men It should also not be ignored that clinical was associated with potentially unwanted research has shown that testosterone interacts changes in triglyceride level (increased) and with thrombophilia-hypoﬁbrinolysis, leading to high density lipoprotein (decreased), which thrombosis. So, decreasing the testosterone could contribute to cardiovascular disease level would prevent testosterone-associated [19, 20]. thrombosis, thus lowering the incidence of Furthermore, Donner et al. found that a cardiovascular disease. Further, it is known that testosterone deﬁciency in diabetic patients was platelet aggregation and stimulation of the related to cardiovascular risk or outcomes . coagulation pathway play important roles in However, their study was limited to animal thrombus formation, and in vitro studies in models in which cardiovascular structure and animal models have shown that reducing function as well as myocardial tolerance were testosterone decreases platelet aggregation and investigated. Daka et al. also showed that a low thromboxane A2 receptor density, thereby testosterone level predicted acute myocardial reducing the incidence of cardiovascular disease infarction in Swedish male patients with T2DM . Even when given at a physiological dosage, . testosterone was shown to increase platelet On the other hand, Herna ´ ndez-Mijares et al. aggregation . Apart from platelet aggrega- did not ﬁnd any association between low tion, testosterone also promotes coagulation by testosterone and the risk of silent myocardial affecting coagulation factors that are implicated infarction or peripheral artery disease, even in the ﬁbrinolytic pathway, resulting in an though their study showed that a low level of increased level of plasminogen activator inhi- testosterone in diabetic male patients was asso- bitor-1 and thus a higher risk of cardiovascular ciated with a high body mass index, a high manifestations due to reduced ﬁbrinolysis . Diabetes Ther (2018) 9:1061–1072 1069 Oral hypoglycemic agents as well as statins given that the testosterone level decreases with have been found to affect the testosterone level age and the use of testosterone ointment by the in male patients with T2DM. While metformin elderly is rising due to an increased rate of is believed to reduce the total testosterone level erectile dysfunction. in male patients with T2DM , glimepiride might, in contrast, help to recover the decreased Novelty testosterone level , whereas the involve- ment of statins in reducing the testosterone This study is new because it is the ﬁrst meta- level is still doubtful . Some of the possible analysis to show that a low level of testosterone iatrogenic causes of testosterone modulation in is a risk factor for CAD/cardiovascular disease in patients with diabetes mellitus are given in patients with T2DM. The results of this study Table 5. may inspire other scientists to investigate this A decreased testosterone level has also been matter further, given that this is potentially an shown to increase vascular disease risk in men important ﬁnding that could be utilized in with hypogonadotropic hypogonadism by clinical medicine. Finally, since it is a new idea indirectly increasing triglyceride levels and low- in the ﬁeld of cardiovascular diabetology, this density lipoprotein levels and decreasing high- analysis is a novelty in itself. density lipoproteins in the blood, which may ultimately contribute to the development of Limitations coronary artery disease . In men who are on antiandrogen therapy (for example patients The limited sample size of the population ana- with prostate cancer), a decreased testosterone lyzed may have inﬂuenced the results. In addi- level may indirectly contribute to cardiovascu- tion, one of the studies considered in this meta- lar diseases, as previously mentioned . In analysis also involved patients who were being patients with diabetes mellitus, other factors treated with testosterone; however, because involving different mechanisms could further that study satisﬁed the inclusion and exclusion raise low-density lipoprotein levels and pro- criteria, it was included in the analysis. More- mote platelet hyperactivity, contributing to over, a moderate level of heterogeneity was cardiovascular diseases . observed during the subgroup analysis. This Nevertheless, cardiovascular disease is one of may have been due to the inclusion of obser- the main complications that arise in patients vational data and other heterogeneous reported with diabetes mellitus. Thus, we believe that the data. Also, the range of testosterone levels var- time has come to review the relationship ied depending on the study, which could be between testosterone level and cardioembolism, another major limitation of this analysis. In addition, the analysis only focused on a partic- ular subgroup of patients with T2DM who did Table 5 Some of the possible iatrogenic causes of testos- not represent the general population of terone modulation in patients with diabetes mellitus patients. Another limitation is the fact that old Medications used in Effect of the medications age is associated with a decreased level of patients with diabetes on the testosterone level testosterone; this would have acted as a con- mellitus founding factor, possibly affecting the results. Biguanides Reduce it Sulfonylurea Stabilizes it at normal level CONCLUSION Alpha-glucosidase inhibitors Reduce it A previously or currently decreased testosterone Thiazolidinediones Reduce it level did not show a statistically signiﬁcant association with a higher risk of CAD/cardio- Insulin Stabilizes it at normal level vascular disease in male patients with T2DM, 1070 Diabetes Ther (2018) 9:1061–1072 although the difference in risk between the Open Access. This article is distributed T2DM patients with low and normal testos- under the terms of the Creative Commons terone levels was observed to approach statisti- Attribution-NonCommercial 4.0 International cal signiﬁcance. The limited number of patients License (http://creativecommons.org/licenses/ analyzed was not sufﬁcient to prove this asso- by-nc/4.0/), which permits any non- ciation, thus warranting further investigations. commercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, ACKNOWLEDGEMENTS and indicate if changes were made. Funding. The research for this study was supported by grants from the National Natural REFERENCES Science Foundation of China (no. 81560046), the Guangxi Natural Science Foundation (no. 1. Tan KH, Barr ELM, Koshkina V, Ma S, Kowlessur S, 2016GXNSFAA380002), the Scientiﬁc Project of Magliano DJ, Soderberg S, Chia KS, Zimmet P, Lim Guangxi Higher Education (no. KY2015ZD028), WY. Diabetes mellitus prevalence is increasing in the Science Research and Technology Develop- South Asians but is stable in Chinese living in Sin- gapore and Mauritius. 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Diabetes Therapy – Springer Journals
Published: Apr 4, 2018
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