Abstract
Objective:
To determine burden and identify correlates of erectile dysfunction (ED) among men with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS).
Research Design and Methods:
The 2017 DPPOS visit included administration of the International Index of Erectile Function. Of 648 male participants, 88% (n=568) completed the survey. Associations between sociodemographic, behavioral, clinical, and glycemic measures at time of ED assessment, and ED were examined using multivariable logistic regression models in men with PreD and T2D separately.
Results:
Overall, 218 (38%) men met ED criteria. Prevalence was similar in men with PreD (41%) and T2D (37%) (p=0.4). In all men, age (p<0.001) increased odds of ED. Among men with PreD, those assigned to intensive lifestyle intervention (ILS), but not metformin, had decreased odds of ED compared with the placebo group (OR=0.35, 95%CI=0.13, 0.94). Non-Hispanic White race was associated with increased odds of ED compared with other races (OR=4.3; 95%CI=1.92, 9.65). Among men with T2D, ED risk did not differ by DPP treatment assignment; however, individuals with metabolic syndrome defined by National Cholesterol Education Program criteria, had increased odds of ED (OR=1.85, 95%CI=1.14, 3.01), as did individuals with depression (OR=2.05; 95%CI=1.10, 3.79).
Conclusions:
ED is prevalent in men with PreD and T2D. Our finding of reduced odds of ED in men randomized to ILS and with PreD suggests a potential opportunity for risk mitigation in the prediabetes interval. In men who have progressed to T2D, metabolic factors appear to be associated with ED.
Keywords: prediabetes, diabetes, erectile dysfunction
INTRODUCTION
Erectile dysfunction (ED), defined as the persistent inability to achieve or maintain a penile erection for satisfactory sexual intercourse,1 is an age-dependent disorder with a trajectory significantly accelerated by diabetes.2 ED generally presents 10–15 years earlier in men with diabetes than in the general population, is more severe, and less responsive to pharmacological therapy.3 Findings from the Epidemiology of Diabetes, Interventions and Complications (EDIC) study showed that 45% of men with longstanding type 1 diabetes (T1D) reported ED.4 Poor glycemic control and cardiovascular autonomic neuropathy were most strongly associated with ED in this cohort.5–7 Although, a meta-analysis of available epidemiological data found a higher prevalence of ED in men with type 2 diabetes (T2D) (66.3%) than those with T1D (37.5%),8 data on the risk factors profiles for ED in T2D from large cohorts with T2D is limited.
The continuous rise in diabetes prevalence over the past few decades,9 has also highlighted the potential impact of prediabetes (PreD), defined as the intermediate metabolic state between normoglycemia and T2D, which includes high fasting glucose, impaired glucose tolerance, insulin resistance and elevated HbA1c concentrations.10 In a recent meta-analysis of 9 studies with 10,980 men, PreD was associated with higher prevalence of ED independent of age.11 Similar risk factors such as hypertension, cardiovascular disease and obesity, for the increased risk of ED in T2 have been hypothesized in PreD,12 however, comprehensive data defining the burden, impact, and risk reduction strategies among people who have abnormal glucose metabolism, but have not yet developed diabetes, are limited. Thus, analyzing differences in the risk factors profiles across the continuum of dysglycemia from its earlier phases to overt T2D could help more accurately estimate the future burden of ED and determine strategies for prevention and intervention.
The Diabetes Prevention Program (DPP), a randomized controlled trial of overweight and obese men and women at high risk for T2D,13 together with its observational follow up, the Diabetes Prevention Program Observational Study (DPPOS),14 offered a unique opportunity to assess ED in middle-aged to older adults whose PreD did or did not convert to T2D. The aim of this study is to gain a deeper understanding of predictive and protective factors for ED in men with dysglycemia due to PreD and incident T2D.
RESEARCH DESIGN AND METHODS
Study Population
The DPP study, a randomized controlled trial conducted between 1996–2001 at 27 clinical centers in the U.S., evaluated the efficacy of two interventions - intensive lifestyle intervention (ILS) and metformin - relative to a control group in preventing or delaying the development of T2D. Eligibility criteria included age ≥25 years, glucose intolerance (defined as fasting plasma glucose of 95–125 mg/dl and 2-hour plasma glucose of 140–200 mg/dl following a 75g oral-glucose load), and body mass index (BMI) ≥24 kg/m2. Participants were randomly assigned to one of three interventions: 1) standard lifestyle recommendations plus placebo twice daily (placebo), 2) standard lifestyle recommendations plus twice daily 850mg of metformin (metformin), and 3) ILS. The goal for the ILS participants was to achieve and maintain a weight reduction of at least 7% of initial body weight through a healthy, low-fat diet and by engaging in moderate intensity physical activity such as brisk walking for at least 150 min/week. Over a median follow-up of 2.8 years, ILS and metformin were associated with 58% and 31% reduced risk, respectively, for diabetes relative to placebo.15 At the conclusion of the DPP phase, all participants including the placebo arm were offered the lifestyle modification program. Participants originally assigned to metformin continued open-label metformin therapy. The DPPOS is a long-term observational follow up of the DPP cohort to understand the clinical course of impaired glucose tolerance, new-onset T2D, and its complications.14 All active DPP participants were eligible for continued follow up in the DPPOS. A total of 2779 (88.5%) of the 3234 DPP participants enrolled in the DPPOS in 2002. Annual assessments during the DPPOS included history and physical examinations, overall health status and quality of life, inventory of all medications, and testing for new onset of T2D, and presence of diabetic complications. In 2017 (Year 15 of the DPPOS), the International Index of Erectile Function (IIEF) questionnaire was administered.16 Of the 648 male participants who completed Year 15, 88% (n=568) completed the IIEF.
Data Collection
At DPP baseline, all participants completed a questionnaire reporting sex, age, self-identified race/ethnicity, and marital status. At DPPOS annual visits, participants were also asked about smoking history, alcohol use, physician-diagnosed medical conditions, and self-rated overall health status. Participants also completed the Beck Depression Inventory, second edition (BDI-II)17 annually in DPPOS until year 12, and again at the year 15 DPPOS visit. For the current analysis, depression was defined as BDI-II total score ≥14 or current use of antidepressant medications at time of ED assessment (DPPOS year 15). Body weight, height, waist circumference, and systolic and diastolic blood pressure were measured annually at designated clinical visits. Physical activity was assessed annually from DPP baseline until DPPOS year 12, with the Modifiable Activity Questionnaire, and was calculated as the product of the duration and frequency of each activity, weighted by an estimate of the metabolic equivalent of that activity and summed for all activities, resulting in estimated average metabolic equivalent (MET) hours per week.18 Diabetic peripheral neuropathy (DPN) was assessed annually in DPPOS using the Michigan Neuropathy Screening Instrument (MNSI)19, a validated instrument with high sensitivity and specificity for DPN, comprised of a 15-item symptom questionnaire and a structured foot examination, plus assessment of ankle reflexes and distal vibration perception. Electrocardiograms (ECGs) were recorded at annually throughout DPP and DPPOS using MAC PC-DT electrocardiographs (Marquette Electronics, Milwaukee, WI).20 The following measures of autonomic function were generated and recorded: maximum QT duration, mean heart rate, the standard deviation of all normal-to-normal R-R intervals (SDNN) (milliseconds), and the root mean square of successive differences between all normal-to-normal R-R intervals (rMSSD) (milliseconds). QT intervals were corrected for heart rate using the QT index (QTI) [measured QT/predicted QT) X 100, where the predicted QT = 656/(1+0.01*heart rate).20 Abnormal SDNN and rMSSD were derived from race-specific ranges per O’Neal et. al.21 Glycemia was measured semi-annually in DPP and DPPOS among all participants with the following measures: fasting glucose, HbA1c, and fasting insulin. The 2-h post challenge 75-gram oral glucose tolerance test (OGTT) was administered semi-annually in DPP and DPPOS among all participants without diabetes. Diagnostic assessment for T2D was performed semi-annually using the American Diabetes Association 1997 guidelines: fasting plasma glucose level ≥126 mg/dL (7.0 mmol/l) or 2-plasma glucose level ≥200 mg/dL (11.1 mmol/l) after OGTT.22 Diagnosis required a confirmation test within 6 weeks. Metabolic syndrome (MetS) was defined based on criteria of the National Cholesterol Education Program Adult Treatment Panel III – with patients having at least three of the following criteria: abdominal obesity, elevated triglycerides, reduced levels of HDL cholesterol, high blood pressure, and high fasting blood glucose levels.23
Outcome Ascertainment
ED was assessed by self-report with the IIEF, a reliable, validated instrument that has been used widely in clinical trials and epidemiological surveys.16 Presence of ED was examined using a number of definitions based on the IIEF Erectile Function subscale including 1) ED severity based on established cut points ranging from None, Mild, Mild to Moderate, Moderate, and Severe; and 2) a proxy item using participant responses to Question 15: “Over the past 4 weeks, how would you rate your confidence that you get and keep your erection?” Those who answered ‘Very Low’ or ‘Low’ were classified as having ED. Those who answered ‘Moderate’, ‘High’, or ‘Very High’ were classified as not having ED. Additionally, those participants using prescribed erectile dysfunction medications (sildenafil, tadalafil, vardenafil, avanafil) were determined to have ED. All final analyses were conducted using the single item proxy as it assessed erectile function regardless of sexual activity and presence or absence of a partner. This definition of ED has been used extensively in the EDIC cohort and correlates strongly with total erectile function domain scores (r=0·77, p<0·001) and ED bother (r=0·80, p<0·001).5
Statistical Analysis
Prevalence of ED was defined as the proportion of participants who met criteria for ED based on IIEF criteria defined above at DPPOS year 15 overall and was compared across treatment groups using χ2 tests for heterogeneity; pairwise comparisons of the lifestyle and metformin arms with placebo were conducted. Sociodemographic, clinical, and diabetes variables were also examined by ED status using χ2 tests, Wilcoxon two-sample tests, and Kruskal-Wallis, as appropriate. Multivariable logistic regression models, using backwards selection of all variables significant at p<0.1 in bivariate analyses, were built in men with PreD (those whose PreD at DPP baseline had not converted to T2D at DPPOS year15) and T2D separately. We considered various forms of time varying exposures (DPPOS year 15 and summary mean defined as mean value over time in DPPOS).
RESULTS
Participant Characteristics
Participant characteristics are presented in Table 1. The average age of the cohort was 71 years +/− 9.3 at the time of ED assessment. Participants’ average BMI was 30.7 and average HbA1c was 6.5% (Table 1). Overall, 177 (31%) men had PreD and 391 (69%) had a diagnosis of T2D.
Table 1.
Characteristics of Men in the DPPOS at Year 15 by ED status (N=568)
| Overall (n=568) | ED (n=218) | No ED (n=350) | p-value | age-adjusted p-value | |||||
|---|---|---|---|---|---|---|---|---|---|
| Group assignment | 0.60 | ||||||||
| Placebo (%) | 182 (32%) | 74 (33.9%) | 108 (30.9%) | ref | ref | ||||
| Metformin (%) | 206 (36.3%) | 80 (36.7%) | 126 (36%) | 0.71 | 0.63 | ||||
| Lifestyle (%) | 180 (31.7%) | 64 (29.4%) | 116 (33.1%) | 0.32 | 0.33 | ||||
| Sociodemographics | |||||||||
| Age (years) | 71.0 ± 9.3 | 74.5 ± 9 | 68.8 ± 8.8 | <0.001 | -- | ||||
| Race/ethnicity (%) | <0.001 | ||||||||
| White | 314 (55.3%) | 144 (66.1%) | 170 (48.6%) | ref | ref | ||||
| African American | 90 (15.8%) | 24 (11%) | 66 (18.9%) | 0.001 | 0.001 | ||||
| Hispanic | 102 (18%) | 31 (14.2%) | 71 (20.3%) | 0.006 | 0.01 | ||||
| Native American/Asian | 62 (10.9%) | 19 (8.7%) | 43 (12.3%) | 0.03 | 0.35 | ||||
| Marital Status (%) | 0.30 | ||||||||
| Never married | 62 (10.9%) | 20 (9.2%) | 42 (12%) | ref | ref | ||||
| Living together/Married | 439 (77.3%) | 176 (80.7%) | 263 (75.1%) | 0.24 | 0.80 | ||||
| Separated/Divorced/Widowed | 67 (11.8%) | 22 (10.1%) | 45 (12.9%) | 0.94 | 0.28 | ||||
| Clinical/Behavioral | |||||||||
| Current Smoking (%) | 9 (1.6%) | 4 (1.9%) | 5 (1.4%) | 0.735** | 0.32 | ||||
| Weekly Alcohol Use (%) | 209 (37.5%) | 67 (31.9%) | 142 (40.8%) | 0.04 | 0.06 | ||||
| General Health (%) | 0.004 | ||||||||
| Excellent/very good | 138 (24.3%) | 51 (23.5%) | 87 (24.9%) | ref | ref | ||||
| Good | 349 (61.6%) | 122 (56.2%) | 227 (64.9%) | 0.68 | 0.27 | ||||
| Fair/poor | 80 (14.1%) | 44 (20.3%) | 36 (10.3%) | 0.01 | 0.05 | ||||
| Depression (%) | 80 (14.9%) | 36 (18%) | 44 (13.1%) | 0.16 | 0.01 | ||||
| Physical Activity (MET/week) (year 12) | 20.6 ± 20.9 | 19.6 ± 20.8 | 21.2 ± 21 | 0.40 | 0.30 | ||||
| Summary mean Physical Activity (MET/week) | 22.2±17.3 | 22.3±17.4 | 21.2±15.3 | 0.440 | 0.85 | ||||
| Body Mass Index (kg/m2) | 30.7 ± 6 | 30.5 ± 5.7 | 30.8 ± 6.2 | 0.65 | 0.12 | ||||
| BMI <25 | 81 (14.2%) | 28 (15.4%) | 25 (12.1%) | 0.57 | 0.62 | ||||
| BMI 25+ | 489 (85.8%) | 154 (84.6%) | 181 (87.9%) | ||||||
| Waist Circumference (cm) | 108.7 ± 14.4 | 110.2 ± 13.4 | 107.7 ± 14.9 | 0.04 | 0.001 | ||||
| PDE5 Inhibitor use (%) | 12 (2.1%) | 12 (5.5%) | 0 (0%) | <0.001 | <0.001 | ||||
| Testosterone (pg/mL) | 3234.9 ± 1159.5 | 3200.9 ± 1077.4 | 3256.4 ± 1209.8 | 0.58 | 0.23 | ||||
| CVD Risk Factors | |||||||||
| JNC Hypertension Status (%) | 0.06 | ||||||||
| Hypertensive | 396 (73.9%) | 158 (79%) | 238 (70.8%) | 0.45 | 0.60 | ||||
| Prehypertensive | 77 (14.4%) | 20 (10%) | 57 (17%) | 0.25 | 0.29 | ||||
| Normotensive | 63 (11.8%) | 22 (11%) | 41 (12.2%) | ref | ref | ||||
| Blood Pressure (mm/Hg) | |||||||||
| Systolic | 123.1 ± 14.6 | 122.8 ± 14.1 | 123.3 ± 14.8 | 0.70 | 0.57 | ||||
| Diastolic | 72 ± 10.3 | 70.8 ± 10.6 | 72.7 ± 10 | 0.03 | 0.795 | ||||
| Antihypertensive use (%) | 381 (71.1%) | 154 (77%) | 227 (67.6%) | 0.03 | 0.05 | ||||
| LDL cholesterol (mg/dL) | 87.2 ± 30.6 | 85.5 ± 28.9 | 88.2 ± 31.5 | 0.32 | 0.73 | ||||
| Summary mean LDL | 99.7 ± 22.6 | 95.4 ± 22.3 | 102.5 ± 22.4 | <0.001 | 0.01 | ||||
| HDL cholesterol (mg/dL) | 49 ± 12.3 | 48.3 ± 12.4 | 49.4 ± 12.2 | 0.30 | 0.02 | ||||
| Summary mean HDL | 45.3 ± 9.7 | 44.8 ± 10.5 | 45.6 ± 9.1 | 0.33 | 0.03 | ||||
| Triglycerides (mg/dL) | 126 ± 74.8 | 119.9 ± 60.4 | 129.7 ± 82.1 | 0.11 | 0.68 | ||||
| Summary mean triglycerides | 140.6 ± 65.4 | 138.2 ± 64.4 | 142.1 ± 66.1 | 0.49 | 0.45 | ||||
| Metabolic syndrome (%) | 314 (55.3%) | 121 (55.5%) | 193 (55.1%) | 0.09 | 0.01 | ||||
| Peripheral and Autonomic Function | |||||||||
| MNSI questionnaire>4 or exam>2 | 268 (49.2%) | 118 (57.3%) | 150 (44.2%) | 0.004 | 0.11 | ||||
| MNSI questionnaire | 1 ± 1.4 | 1.2 ± 1.5 | 0.9 ± 1.4 | 0.02 | 0.08 | ||||
| MNSI questionnaire>4 | 20 (3.6%) | 9 (4.2%) | 11 (3.2%) | 0.68 | 0.60 | ||||
| Summary mean MNSI questionnaire | 0.9 ± 1.0 | 1 ± 1 | 0.8 ± 0.9 | 0.008 | 0.03 | ||||
| MNSI exam | 2.3 ± 1.7 | 2.7 ± 1.8 | 2.1 ± 1.6 | <0.001 | 0.01 | ||||
| MNSI exam>2 | 267 (49%) | 118 (57.3%) | 149 (44%) | 0.003 | 0.09 | ||||
| Summary mean MNSI exam | 1.9 ± 0.9 | 2.1 ± 1 | 1.7 ± 0.9 | <0.001 | 0.008 | ||||
| Heart rate (bpm) | 63.5 ± 11.2 | 63.4 ± 11.1 | 63.6 ± 11.3 | 0.84 | 0.71 | ||||
| Summary mean heart rate (bpm) | 62.8 ± 8.5 | 62.2 ± 8.4 | 63.2 ± 8.6 | 0.17 | 0.75 | ||||
| QTI (%) | 102.6 ± 5.7 | 103.7 ± 7 | 101.9 ± 4.7 | 0.001 | 0.02 | ||||
| Summary mean QTI (%) | 100.6 ± 3.7 | 101.3 ± 4.1 | 100.2 ± 3.3 | <0.001 | 0.01 | ||||
| SDNN (ms) | 26.4 ± 21.6 | 23 ± 16.2 | 28.4 ± 24 | 0.003 | 0.05 | ||||
| Abnormal SDNN (%) | 18 (3.8%) | 6 (3.5%) | 12 (3.9%) | 0.99 | 0.47 | ||||
| Summary mean SDNN (ms) | 13.1 ± 5.8 | 12.9 ± 5.3 | 13.3 ± 6.2 | 0.46 | 0.92 | ||||
| RMSD (ms) | 25 ± 23.3 | 23.1 ± 20.7 | 26.2 ± 24.7 | 0.14 | 0.29 | ||||
| Abnormal RMSD (%) | 25 (5.2%) | 9 (5.2%) | 16 (5.3%) | 1.00 | 0.71 | ||||
| Summary mean RMSD (ms) | 24.4 ± 14.2 | 24.3 ± 13.9 | 24.4 ± 14.4 | 0.94 | 0.96 | ||||
| Diabetes | |||||||||
| Fasting plasma glucose (mg/dL) | 128.6 ± 35.4 | 129.4 ± 40.2 | 128.1 ± 32.1 | 0.70 | 0.16 | ||||
| Summary mean fasting glucose | 118.8 ± 20.4 | 118.9 ± 21.7 | 118.7 ± 19.6 | 0.92 | 0.23 | ||||
| HbA1c (%) | 6.5 ± 1.4 | 6.5 ± 1.6 | 6.5 ± 1.3 | 0.85 | 0.23 | ||||
| Summary mean HbA1c | 2.3 ± 1.5 | 2.3 ± 1.6 | 2.3 ± 1.5 | 0.79 | 0.23 | ||||
| Fasting insulin (μU/mL) | 30.8 ± 25.5 | 32.5 ± 32.1 | 29.8 ± 20.5 | 0.29 | 0.23* | ||||
| Summary mean fasting insulin | 30.4 ± 16.0 | 3.2 ± 0.7 | 3.2 ± 0.6 | 0.85 | 0.43* | ||||
| HOMA-IR | 10.0±10.0 | 9.7±7.1 | 10.8±13.5 | 0.27 | 0.01 | ||||
| Summary mean HOMA-IR | 8.8±5.4 | 8.7±5.0 | 8.9±6.0 | 0.80 | 0.10 | ||||
| Type 2 diabetes (%) | 391 (68.8%) | 145 (66.5%) | 246 (70.3%) | 0.40 | 0.84 | ||||
| Duration of diabetes (years) | 7.9 ± 7.1 | 8.1 ± 7.4 | 7.7 ± 7 | 0.48 | 0.35 | ||||
| Medication use*** | 306 (53.9%) | 120 (55.1%) | 186 (53.1%) | 0.66 | 0.08 | ||||
| Metformin | 267 (50.5%) | 101 (50.8%) | 166 (50.3%) | 0.92 | 0.14 | ||||
| Sulfonylureas | 14 (5.1%) | 5 (4.9%) | 9 (5.2%) | 0.90 | 0.96 | ||||
| Insulin | 8 (3.0%) | 6 (5.8%) | 2 (1.2%) | 0.06** | 0.02 | ||||
| DPP-4 inhibitors | 4 (1.5%) | 2 (2.0) | 2 (2.0) | 0.63** | 0.65 | ||||
| GLP-1 receptor antagonists | 3 (1.1%) | 1 (1.0%) | 2 (1.2%) | 1.00** | 0.76 | ||||
| Thiazolidinediones | 9 (3.3%) | 4 (3.9%) | 5 (3.0%) | 0.73** | 0.82 | ||||
| Meglitinides | 1 (0.4%) | 1 (1.0%) | 0 (0.0%) | 0.38** | 0.15 | ||||
| Diabetes Complications | |||||||||
| Nephropathy | 160 (28.3%) | 75 (34.4%) | 85 (24.3%) | 0.009 | 0.07 | ||||
| eGFR | 77.7±18.2 | 73.9±19.7 | 80.2±16.9 | <0.001 | 0.33 | ||||
| eGFR < 45 | 28 (4.9%) | 18 (8.3%) | 10 (2.9%) | 0.004 | 0.15 | ||||
| Summary mean eGFR | 86.0±14.2 | 82.8±15.5 | 88.0±13.0 | <0.001 | 0.37 | ||||
| Retinopathy | 75 (13.2%) | 32 (14.7%) | 43 (12.3%) | 0.41 | 0.36 | ||||
Note: Summary mean measures represent 15-year mean values from DPPOS baseline to DPPOS year 15
p-value based on differences in log of mean values
Fisher’s Exact test
Medication use is any diabetes medication use. All p-values shown use “no medication use” as the reference group. Abbreviations: DPPOS= Diabetes Prevention Program Outcomes Study, ED= erectile dysfunction, MET=metabolic equivalent of task, BMI= body mass index, PDE5=Phosphodiesterase 5, JNC= Joint National Committee, LDL= low density lipoprotein, HDL= high density lipoprotein, MNSI= Michigan Neuropathy Screening Instrument, QTI= individualized QT interval, SDNN=standard deviation of NN intervals, RMSD= root mean square of successive RR interval differences, HbA1c= hemoglobin A1C, HOMA-IR=Homeostatic Model Assessment for Insulin Resistance, DPP-4= Dipeptidyl peptidase 4, GLP-1= Glucagon-like peptide-1
Erectile Dysfunction Prevalence and Associated Factors
The prevalence of ED in the overall cohort was 38.4% based on participants responses to the single item proxy (Figure 1). About a third of the population overall self-reported ‘high’ or ‘very high’ level of confidence in achieving and maintaining an erection. Nine of the men who self-reported “very high” confidence on the proxy item were reclassified as having ED based on medication use. Men with ED were older (p<0.001), and after adjustment for age, greater proportions of men with ED were non-Hispanic white (p=0.001), reported poorer general health (p=0.01), and met the study criteria for depression (p=0.01), compared to those with no ED (Table 1). Additionally, men with ED were more likely to have DPN based on higher summary mean MNSI exam (p=0.008) and questionnaire (p=0.03) scores and autonomic neuropathy based on higher DPPOS year 15 QTI (p=0.02) and lower SDNN (p<0.05) compared to those without ED. Neither the HbA1c level, presence of T2D nor diabetes duration were associated with ED; however, the proportion of men who met metabolic syndrome criteria at time of ED assessment was found to be significantly higher (p=0.01) among men with ED compared to men who did not report ED, along with waist circumference (p=0.001), and antihypertensive use (p=0.05). While mean MET/week were lower among men with ED compared to men without ED (19.6 vs. 21.2, p=0.30), this finding was not statistically significant.
Figure 1.
Distribution of Responses to ED Single Item Proxy Overall and by Diabetes Status
* 9 (1.6%) additional participants added to cohort of participants with ED based on criteria of PDE5-Inhibitor use
Erectile Dysfunction and DPP Randomization
When analyzed based on prior interventions arms, ED was observed in 40.7%, 38.8%, and 35.6% in the former DPP placebo, metformin, and ILS intervention groups respectively. These differences were not significantly different. In exploratory analyses using the multi-categorical ED definition (Supplemental Table 1), a significant difference in ED rates by DPP treatment group was observed. A higher proportion of severe ED was observed in the placebo arm (52.8%) compared to the metformin arm (41.6%) while higher proportions of men with no ED were observed in the metformin (21.8%) and ILL (20.8%) arms compared to the placebo arm (28.3%) (overall p=0.003). The protective effect of metformin was not statistically significant in subsequent multivariable adjusted models.
Prediabetes and Type 2 Diabetes Comparison
The prevalence of ED was similar in men with PreD (41%) and T2D (37%) (p=0.4). In comparing the PreD and T2D cohort on other factors, notable differences included younger age, higher BMI and waist circumference, higher prevalence of hypertension, lower HDL, and a higher triglyceride level in the T2D cohort (Supplemental Table 2). These differences in measures of obesity, blood pressure and lipids conferred higher rates of metabolic syndrome in those with T2D compared to men in the PreD group.
Multivariable Regression Findings on Odds of Erectile Dysfunction
Separate multivariable analyses were run in men with PreD and in men with T2D. In both models, higher odds of ED were noted with older age (Table 2). In the model examining only men with PreD, in addition to the findings of age, we observed that non-Hispanic white race was significantly associated with ED (OR=4.30, 95%CI=1.92, 9.65) and those assigned to ILS, but not metformin, had decreased odds of ED compared with the placebo group (OR=0.35, 95%CI=0.13, 0.94). Treatment group and race were not associated with ED in the model examining only men with T2D. Rather, the presence of depression (OR=2.05, 95%CI=1.10, 3.79) and metabolic syndrome (OR=1.85, 95%CI=1.14, 3.01) at time of ED assessment were significantly associated with increased odds of ED in men with T2D.
Table 2.
Multivariable Adjusted Odds Ratios for ED in Men by Type 2 Diabetes Status at Year 15
| Odds Ratio (95% CI) | p-value | |
|---|---|---|
| Model 1: Men with T2D at DPPOS year 15 | ||
| DPP Group assignment | ||
| Placebo | ref | |
| Metformin | 0.82 (0.48, 1.45) | 0.48 |
| Lifestyle | 0.83 (0.48, 1.42) | 0.52 |
| Age | 1.07 (1.04, 1.10) | <0.001 |
| Depression | 2.05 (1.10, 3.79) | 0.02 |
| Metabolic syndrome | 1.85 (1.14, 3.01) | 0.01 |
| Model 2: Men with Prediabetes at DPPOS year 15 | ||
| DPP Group assignment | ||
| Placebo | ref | |
| Metformin | 0.72 (0.30, 1.87) | 0.48 |
| Lifestyle | 0.35 (0.13, 0.94) | 0.04 |
| Age | 1.10 (1.05, 1.16) | <0.001 |
| Non-Hispanic white race | 4.30 (1.92, 9.65) | <0.001 |
Note: Based on two separate backward selection process multivariable logistic regression models with only significant variables retained. DPP treatment group assignment was forced in. Variables listed in each model are adjusted for all others included.
Abbreviations: DPPOS= Diabetes Prevention Program Outcomes Study, ED= erectile dysfunction, T2D= type 2 diabetes
DISCUSSION
In this study of male participants of the DPPOS, we observed that ED is equally prevalent in men at risk for T2D (PreD) as in those with T2D. DPP assignment to the ILS intervention group was associated with substantially lower odds of prevalent ED at DPPOS year 15 in the men who did not progress to T2D. In contrast, no association between DPP treatment assignment and prevalence of ED was found in men who developed T2D. In men with T2D, the association of the metabolic syndrome with higher odds of ED suggests that factors other than glycemia such as blood pressure and lipid abnormalities contribute to the pathogenesis of ED in T2D.
With the growing burden of diabetes globally, there has been an increasing body of work assessing the resultant complications of diabetes such as ED.24 Population based studies have shown that ED is more common in persons with diabetes compared to the general population,3,24 with a prevalence reported in the literature ranging from 35% to 90%.12,25 We observed an overall prevalence of ED of 38% in men with prediabetes or incident T2D. While this is on the lower end of the range from previously published reports 4,26, we used a conservative definition of ED (independent of partner status) in this cohort comprising men who report very low to low confidence in getting and keeping an erection in order to focus on those who experience persistent and clinically significant difficulties. An additional 30% of men fell in the ‘moderate’ category which was not included in our definition of ED. (Supplemental Table 1) Including the men in the moderate category did not significantly alter findings presented in the current report ( i.e., similar effects sizes for risk factors were observed albeit some lost statistical significance) (data not shown). Consistent with the body of evidence in populations of men with both diabetes and without, we observed significant increased odds of ED with older age in both men with PreD and T2D, depression in men with T2D, and non-Hispanic white race in men with PreD.3,11,25
In the current study, DPP assignment to lifestyle intervention was associated with lower odds of ED compared to the placebo arm among men with PreD. This finding is consistent with studies both in the general population and in T2D that report that physical activity can contribute to a reduction in ED.27,28 In a meta-analysis of population-based studies, a significant dose response effect was observed between physical activity levels and odds of ED with higher levels of physical activity conferring lower odds of ED and minimal activity conferring the highest odds of ED.29 The protective effect observed in our study could be a result of the direct impact of physical activity on erectile function via improved cardiovascular, neurological, endothelial and metabolic profiles or indirectly by preventing early hyperglycemia exposure and subsequent diabetic complications related to ED. The DPP randomized ILS intervention resulted not only in a significant reduction in incident diabetes but significant improvement in indexes that reflect autonomic function and fitness which could have resulted in reduced rates of ED.20 Importantly several studies have demonstrated the impact of early intervention on at risk non-diabetic populations20 including reduced incidence of hypertension, cardiovascular events, and aggregate microvascular disease.30,31 In the Look AHEAD (Action for Health in Diabetes) trial which compared ILS intervention to diabetes support and education in overweight and obese type 2 diabetes patients,32,33 cardiorespiratory fitness was found to be protective of ED. Authors theorized that increased physical activity led to improved insulin sensitivity and nitric oxide regulation.33 It is important to note that in the current study while physical activity levels were lower at the time of ED assessment in men with ED compared to men without ED, these findings were not statistically significant. Further the initial trial was not designed to test the relative contributions of dietary changes, increased physical activity, and weight loss therefore the effect of the specific contribution of physical activity both early on and over time on the reduction of ED remains to be determined. Additionally, following the DPP end and at the onset of the DPPOS, lifestyle help sessions were offered to participants every 3 months, with provision of educational materials to reinforce the original trial weight loss and physical activity goals. In addition, supplementary programs were offered to reinvigorate self-management behaviors for weight loss14. This active long-term engagement to encourage participant adherence to lifestyle behaviors could have also influenced current findings. Interestingly, the results of the DPPOS overall demonstrated durable long-term effects of the original DDP interventions on the cumulative incidence of diabetes 15 years later14. We hypothesize that the ultimate benefit of ED mitigation from earlier intervention is due to potential reduction of hyperglycemia and subsequent development of diabetes and its complications (neuropathy, micro- macrovascular disease) and comorbidities (metabolic syndrome) which have been demonstrated to increase risk for ED. In summary, the protective effect of ILS assignment on ED finding suggests potentially that early intervention of at least physical activity and/or weight loss may contribute to reduction in ED risk in those at risk for but who have not yet developed T2D.
In men with established T2D, who made up two thirds of the DPPOS cohort at Year 17, after accounting for age, we observed a strong and significant association between the presence of metabolic syndrome and ED. Further analysis, however, did not demonstrate a difference in ED burden by treatment arm as observed in the PreD group. This may indicate that at a certain threshold of glycemia the protective effects observed in the PreD group no longer have an impact. Participants in our study with T2D had higher rates of metabolic syndrome compared to participants with prediabetes (68.3% vs. 26.6%, p<0.001). Our findings are consistent with reports in the literature that has identified metabolic syndrome not only to be highly prevalent in men with erectile dysfunction34 but also an independent risk factor for ED.35,36 Metabolic syndrome may lead to ED through multiple mechanisms: 1) atherosclerotic disease may lead to ED by affecting the vascular tissues of the penis, 2) endothelial dysfunction leads to a decrease in vascular nitric oxide levels, with resulting impaired vasodilation, 3) hyperglycemia can cause glycation of penile cavernosal tissue leading to impairment of collagen turnover and subsequent ED and can also lead to endothelial dysfunction by upregulation of E‐selectin and altered tumor necrosis factor‐α and interleukin‐10 ratio.37,38 and 4) hypogonadism in obesity due to decreased production of testosterone and increased aromatization to estrogen is associated with ED. In comparing the PreD and T2D population (Supplemental Table 2), significant differences were observed in BMI and waist circumference as well as testosterone levels likely contributing to the higher rates of metabolic syndrome observed in the T2D cohort.
While an early pilot clinical trial observed that sexual function improved after addition of metformin to patients who had ED but responded poorly to sildenafil,39 subsequent observational studies suggested the contrary. These studies reported increased risks of ED in patients with diabetes who had used metformin.40,41 Interestingly, the clinical trial that showed a benefit of metformin on ED included men without diabetes but had insulin resistance while the later studies suggesting a potential adverse effect were conducted in patients with frank diabetes. In long standing diabetes, men likely present with well-established and chronic ED where endothelial dysfunction is more advanced and potentially irreversible. The effect size of therapies like metformin may be diminished in these populations, however the potential benefit may be much more substantial for men studied at earlier stages of both diabetes and erectile dysfunction.42 While we observed protective effects of randomization to metformin in both the PreD and T2D cohorts in the current study, these findings were not statistically significant. We hypothesize that this is likely due to the positive impact of diet, exercise and psychological factors on the mechanism for ED in metabolic syndrome.
Although our study provides a comprehensive assessment of the associations between sociodemographic, clinical, behavioral and diabetes characteristics and erectile dysfunction measured using validated instruments in the setting of PreD and T2D, there are several limitations that should be considered. First, there is potential bias due to a differential disease experience (sexual dysfunction) for subjects lost to follow-up. A great deal of effort is devoted to reducing loss to follow-up as evidenced by a response rate of >88% since DPPOS baseline. Second, there is potential for temporal sequence bias as sexual dysfunction was only assessed at one time point (DPPOS year 15). We do not have information on whether the DPP intervention and other risk factors (i.e., depression) preceded ED status or was a consequence of ED. Third, while the careful randomization that took place in the DPP was successful in distributing potentially confounding factors evenly across study arms, our results could still be impacted by residual confounding from factors unmeasured in DPPOS such as medication effects, psychosocial factors, ischemic heart disease and peripheral vascular disease all known to impact ED. Fourth, it should be noted that PreD is a potentially transient state that can be stable or change to normal glucose regulation (NGR) or diabetes. A small percentage of participants originally classified as having PreD could have returned to NGR and not captured in our cross-sectional analysis. Further, while we assume the vast majority of participants in the DPPOS with diabetes have T2D, some had diabetes autoimmunity markers at baseline, and some had progressed to insulin treatment. Therefore, it is possible that a few have type 1 diabetes (T1D) or latent autoimmune diabetes in adults (LADA). Some had maturity onset diabetes of the young (MODY) susceptibility gene variants so may have developed monogenetic diabetes rather than T2D. Fifth, as a secondary analysis of the DPPOS, the stratified samples of PreD and T2D may not be adequately powered for ED point estimates. Finally, there is a potential problem in extrapolating findings from this study to the general population of men with or at high risk for T2D. Participants in this study were provided diabetes management that was/is perhaps better than the standard, possibly limiting our power to detect effects of diabetes-specific mechanisms on sexual dysfunction. However, published data from our work in the DCCT/EDIC have previously demonstrated significant effects of diabetes related characteristics on ED in men with type 1 diabetes in a trial and observational study setting and we have no reason to believe that factors that we identify in this cohort would not be similar to other groups of men with or at high risk for type 2 diabetes.
CONCLUSION
ED is prevalent in men with PreD and with T2D. In addition to known risk factors for ED typically observed in the general population, such as older age, assignment to ILS intervention was associated with decreased odds of ED in men with PreD and at increased risk for T2D. In men with T2D, our findings suggest metabolic syndrome is associated with ED in T2D. This study identifies important characteristics associated with ED in both the PreD and T2D populations within the context of a large longitudinal study. Future prospective studies may be able to corroborate these initial insights into risk and risk reduction of ED. Given the significant burden of PreD and T2D, targeted preventative strategies, early markers of risk, and information on timing to intervene on this patient population are urgently needed.
Supplementary Material
Highlights.
Erectile dysfunction is prevalent in men with prediabetes and type 2 diabetes.
Reduced odds of ED in men randomized to ILS and with PreD suggests a potential opportunity for risk mitigation in the prediabetes interval.
In men who have progressed to T2D, metabolic factors appear to be associated with ED.
Funding and Assistance:
This study was supported by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255.
Further, the DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, U01 DK048400, U01 DK076169 and U01 DK115255 by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication. All authors in the writing group had access to all data. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies. A complete list of Centers, investigators, and staff can be found in the Appendix.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of Interest: No conflicts of interest.
REFERENCES
- 1.Institutes N and Health OF: Impotence: NIH Consensus Development Panel on Impotence. JAMA J. Am. Med. Assoc 1993; 270: 83–90. [PubMed] [Google Scholar]
- 2.Fedele D: Therapy Insight: sexual and bladder dysfunction associated with diabetes mellitus. Nat Clin Pr. Urol 2005; 2: 282–290. [DOI] [PubMed] [Google Scholar]
- 3.Feldman HA, Goldstein I, Hatzichristou DG, et al. : Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J. Urol 1994. [DOI] [PubMed]
- 4.Wessells H, Braffett BH, Holt SK, et al. : Burden of Urological Complications in Men and Women With Long-standing Type 1 Diabetes in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Cohort. Diabetes Care 2018; 41: 2170–2177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Wessells H, Penson DF, Cleary P, et al. : Effect of Intensive Glycemic Therapy on Erectile Function in Men With Type 1 Diabetes. J. Urol 2011; 185: 1828–1834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Pop-Busui R, Hotaling J, Braffett BH, et al. : Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: findings from the DCCT/EDIC. J Urol 2015; 193: 2045–2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hotaling JM, Sarma AV, Patel DP, et al. : Cardiovascular Autonomic Neuropathy, Sexual Dysfunction, and Urinary Incontinence in Women With Type 1 Diabetes. Diabetes Care 2016; 39: 1587–1593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kouidrat Y, Pizzol D, Cosco T, et al. : High prevalence of erectile dysfunction in diabetes: a systematic review and meta-analysis of 145 studies. Diabet. Med 2017. [DOI] [PubMed]
- 9.Anon: Centers for Disease Control and Prevention. National diabetes statistics report 2020. Available at: www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
- 10.Anon: Standards of Medical Care in Diabetes. Diabetes Care 2017; 40: S1–S135.27979885 [Google Scholar]
- 11.Jin M, Yuan S, Wang B, et al. : Association Between Prediabetes and Erectile Dysfunction: A Meta-Analysis. Front. Endocrinol. (Lausanne) 2022; 12: 1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Malavige LS and Levy JC: Erectile dysfunction in diabetes mellitus. J. Sex. Med 2009. [DOI] [PubMed]
- 13.The Diabetes Prevention Program Research Group: The Diabetes Prevention Program. Baseline characteristics of the randomized cohort. Diabetes Care 2000; 23: 1619–1629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Nathan DM, Barrett-Connor E, Crandall JP, et al. : Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: The Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015. [DOI] [PMC free article] [PubMed]
- 15.Knowler William C., Barrett-Connor Elizabeth, Fowler Sarah E., Hamman Richard F., Lachin John M., Walker Elizabeth A., Nathan David M., Watson PG, Mendoza JT, Smith KA, Caro J, Goldstein B, Lark C, Menefee L, Murphy L, Pepe CJM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Dep. Med. Fac. Pap 2002: Paper 322. [DOI] [PMC free article] [PubMed]
- 16.Rosen RC, Riley A, Wagner G, et al. : The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822–830. [DOI] [PubMed] [Google Scholar]
- 17.Beck AT, Steer RA & Brown GK: Manual for Beck Depression Inventory-II San Antonio, TX; 1996. [Google Scholar]
- 18.Kriska AM, Knowler WC, LaPorte RE, et al. : Development of questionnaire to examine relationship of physical activity and diabetes in Pima Indians. Diabetes Care 1990; 13: 401–411. [DOI] [PubMed] [Google Scholar]
- 19.Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal DAG N: A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17: 1281–1289. [DOI] [PubMed] [Google Scholar]
- 20.Carnethon Mercedes R., Prineas Ronald J., Temprosa Marinella, Zhang Zhu-Ming, Uwaifo Gabriel, Mark E. Molitch for the DPPRG: The Association Among Autonomic Nervous System Function, Incident Diabetes, and Intervention Arm in the Diabetes Prevention Program. Diabetes Care 2006; 29: 914–919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.O’Neal WT, Chen LY, Nazarian S, et al. : Reference ranges for short-term heart rate variability measures in individuals free of cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA). J. Electrocardiol 2016; 49: 686–690. Available at: 10.1016/j.jelectrocard.2016.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Gabir MM, Hanson RL, Dabelea D, et al. : The 1997 American Diabetes Association and 1999 World health Organization Criteria for Hyperglycemia in the Diagnosis and Prediction of Diabetes. Diabetes Care 2000; 23: 1108–1112. [DOI] [PubMed] [Google Scholar]
- 23.Cleeman JI: Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). J. Am. Med. Assoc 2001; 285: 2486–2497. [DOI] [PubMed] [Google Scholar]
- 24.Martin-Morales A, Sanchez-Cruz JJ, Saenz de Tejada I, Rodriguez-Vela L, Jimenez-Cruz JF RB R: Prevalence and independent risk factors for erectile dysfunction in Spain: results of the Epidemiologia de la Disfuncion Erectil Masculina Study. J. Urol 2001; 166: 569–574. [DOI] [PubMed] [Google Scholar]
- 25.Berardis GDE, Pellegrini F, Franciosi M, et al. : IDENTIFYING PATIENTS WITH TYPE 2 DIABETES WITH A HIGHER LIKELIHOOD OF ERECTILE DYSFUNCTION : THE ROLE OF THE INTERACTION BETWEEN CLINICAL AND PSYCHOLOGICAL FACTORS. J. Urol 2003; 169: 1422–1428. [DOI] [PubMed] [Google Scholar]
- 26.Bajaj HS, Gerstein HC, Rao-Melacini P, et al. : Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial. Lancet Diabetes Endocrinol 2021; 9: 484–490. Available at: 10.1016/S2213-8587(21)00115-7. [DOI] [PubMed] [Google Scholar]
- 27.Selvin E, Burnett AL and Platz EA: Prevalence and Risk Factors for Erectile Dysfunction in the US. Am. J. Med 2007; 120: 151–157. [DOI] [PubMed] [Google Scholar]
- 28.Bacon CG, Mittleman MA, Kawachi I, et al. : Sexual Function in Men Older Than 50 Years of Age: Results from the Health Professionals Follow-up Study. Ann. Intern. Med 2003; 139: 161–169. [DOI] [PubMed] [Google Scholar]
- 29.Cheng JYW, Ng EML, Ko JSN, et al. : Physical activity and erectile dysfunction: Meta-analysis of population-based studies. Int. J. Impot. Res 2007; 19: 245–252. [DOI] [PubMed] [Google Scholar]
- 30.Perreault L, Pan Q, Schroeder EB, et al. : Regression from prediabetes to normal glucose regulation and prevalence of microvascular disease in the diabetes prevention program outcomes study (DPPOS). Diabetes Care 2019; 42: 1809–1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Schneider CA: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. Diabetes und Stoffwechsel 2003; 12: 266–268. [Google Scholar]
- 32.Heilbronn L, Ravussin E, Smith S, et al. : Baseline characteristics of the Look AHEAD (Action for Health in Diabetes) trial. Abstr. J Am Diet Assoc 2004; 104: 1–246. [Google Scholar]
- 33.Rosen RC, Wing RR, Schneider S, et al. : Erectile dysfunction in type 2 diabetic men: Relationship to exercise fitness and cardiovascular risk factors in the look ahead trial. J. Sex. Med 2009. [DOI] [PMC free article] [PubMed]
- 34.Bansal Tina C.,* Guay André T.,* Jacobson Jerilynn,* Woods Bartholomew O., † and and Nesto Richard W.: Incidence of Metabolic Syndrome and Insulin Resistance in a Population with Organic Erectile Dysfunction. J. Sex. Med 2005; 2: 96–103. [DOI] [PubMed] [Google Scholar]
- 35.Heidler S, Temml C, Broessner C, et al. : Is the Metabolic Syndrome an Independent Risk Factor for Erectile Dysfunction? J. Urol 2007; 177: 651–654. [DOI] [PubMed] [Google Scholar]
- 36.Bal K, Öder M, Şahin AS, et al. : Prevalence of Metabolic Syndrome and Its Association with Erectile Dysfunction Among Urologic Patients: Metabolic Backgrounds of Erectile Dysfunction. Urology 2007; 69: 356–360. [DOI] [PubMed] [Google Scholar]
- 37.Sanjay S, Bharti G, Manish G, et al. : Metabolic syndrome: An independent risk factor for erectile dysfunction. Indian J. Endocrinol. Metab 2015; 19: 277–282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Fonseca V and Jawa A: Endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: Common pathways and treatments? Am. J. Cardiol 2005; 96: 13–18. [DOI] [PubMed] [Google Scholar]
- 39.Rey-Valzacchi GNJ, Costanzo PR, Finger LA, et al. : Addition of metformin to sildenafil treatment for erectile dysfunction in eugonadal nondiabetic men with insulin resistance. A prospective, randomized, double-blind pilot study. J. Androl 2012; 33: 608–614. [DOI] [PubMed] [Google Scholar]
- 40.Al-Kuraishy HM and Al-Gareeb AI: Erectile dysfunction and low sex drive in men with type 2 DM: The potential role of diabetic pharmacotherapy. J. Clin. Diagnostic Res 2016; 10: FC21–FC26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Abdul-Hadi MH, Naji MT, Shams HA, Sami OM, Al-Kuraishy HM, and Al-Gareeb AI: Erectile Dysfunction and Type 2 Diabetes Mellitus: A New Twist. Int. J. Nutr. Pharmacol. Neurol. Dis | 2020; 10: 43–49. [Google Scholar]
- 42.Patel JP, Lee EH, Mena CI, et al. : Effects of metformin on endothelial health and erectile dysfunction. Transl. Androl. Urol 2017; 6: 556–565. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.