Category: 8. Health

Introduction

Sarcopenia is a progressive disorder characterized by the loss of muscle mass and strength. And it is particularly prevalent among older adults, it might affect up to half of people aged 80 years and older, posing a significant public health challenge. In older adults with type 2 diabetes mellitus (T2DM), the prevalence of sarcopenia is 2–3 times higher than in non-diabetic peers.¹ This dual burden not only impairs physical performance and quality of life but also increases the risk of falls, frailty, and mortality.² In recent years, growing concerns have arisen regarding the potential impact of glucose-lowering medications on muscle health, generating significant clinical debate. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are commonly used hypoglycemic agents. They work through several mechanisms, including increasing glucose-dependent insulin secretion, inhibiting glucagon secretion during hyperglycemia, delaying gastric emptying, and reducing caloric intake. Semaglutide, a long-acting GLP-1RA, can be administered subcutaneously once weekly. It effectively lowers glucose levels and promotes significant weight loss, making it widely adopted for the treatment of diabetes and obesity.^3,4 Additionally, it has shown therapeutic effects on sarcopenic obesity.⁵ However, concerns have been raised about the potential for muscle loss due to long-term Semaglutide use. Some studies indicate that elevated GLP-1 levels may have a detrimental effect on muscle mass.⁶ Given that elderly patients are at a higher risk for sarcopenia, it is essential to further investigate how Semaglutide treatment affects skeletal muscle in this population. In this study, we examined changes in muscle mass and strength among elderly type 2 diabetes patients using Semaglutide, aiming to provide evidence-based guidance for its clinical application.

Methods

Study Design and Participants

This retrospective cohort study investigated older patients (≥65 years) with T2DM who initiated Semaglutide therapy at our hospital between January 2022 and December 2022. Propensity score matching (1:1 ratio) was performed based on age, sex, baseline BMI, diabetes duration, and comorbidities. The resulting control group had comparable baseline characteristics but was not exposed to GLP-1RAs or DPP-4 inhibitors. All participants were monitored for 24 months, with data collected at baseline (0 months), 6 months, 12 months, 18 months, and 24 months. Inclusion criteria were as follows: Age ≥65 years with T2DM (according to ADA guidelines), Body mass index (BMI) ≥24kg/m², with no prior use of GLP-1RA or DPP-4 inhibitors. The study had certain criteria that excluded individuals who had severe liver or renal impairment (defined as serum alanine transaminase (ALT) ≥ 3-fold the upper limit of normal; estimated glomerular filtration rate (eGFR)<15mL/ min/1.73 m²) and cancer. Study subjects meeting the eligibility criteria were included after comprehensive validation of data completeness via the electronic health records system, with exclusion of any cases lacking essential variables. All participants received individualized glucose-lowering regimens supervised by endocrinology specialists. Semaglutide dosage was adjusted based on both glycemic monitoring and hemoglobin A1c levels. This study was approved by the Ethics Committee of Shijiazhuang People’s Hospital (Approval No: 2025075) and conducted by the Declaration of Helsinki. All participants provided written informed consent prior to data collection. Patient confidentiality was protected by anonymizing all personal identifiers in the dataset. The reporting followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Data Collection

Demographic and clinical parameters were systematically extracted from electronic medical records. This data included age, sex, BMI, muscle parameters, duration of diabetes, and comorbidities. The chronic diseases considered included cerebrovascular disease, coronary heart disease, kidney disease, hypertension, and chronic obstructive pulmonary disease (COPD). Due to the retrospective study design, standardized assessments of lifestyle factors (dietary intake and physical activity) were unavailable in the source dataset.

Muscle parameters were assessed through measurements of muscle mass and function. Skeletal muscle mass was estimated using bioelectrical impedance analysis (BCA-1C, Tongfang Health Technology, Beijing). Upper extremity muscle strength was evaluated through handgrip strength measurements, taken with an electronic hand dynamometer (CAMRY EH101, Guangdong). Lower limb muscle strength was evaluated using a 4-meter gait speed test, calculated as gait speed (m/s) = 4 (m) ÷ time (s).

The appendicular skeletal muscle mass index (ASMI) was calculated by dividing the appendicular lean mass of the arms and legs by the square of height (kg/m²). Sarcopenia diagnosis followed 2019 Asian Working Group for Sarcopenia (AWGS) criteria,⁷ requiring both low muscle mass (ASMI <7.0 kg/m² males, <5.7 kg/m² females) and reduced muscle strength (handgrip strength <28 kg males, <18 kg females).

Statistical Analysis

Data were statistically analyzed using IBM SPSS 27.0 and GraphPad 9.0. Continuous variables with normal distribution were expressed as mean ± standard deviation (Mean ± SD). Between-group comparisons used independent samples t-tests, while intra-group longitudinal changes were analyzed with paired t-tests. Categorical variables were compared via chi-square tests. Multivariable linear regression models were constructed to identify clinical predictors of accelerated muscle loss during Semaglutide treatment, adjusting for potential confounders. A two-tailed p-value <0.05 defined statistical significance.

Results

The analysis included 220 Semaglutide-treated patients and 212 matched controls. The baseline information of the Semaglutide treatment group is shown in Table 1. Sarcopenia prevalence was 27.73% in the study population. No significant differences were observed in baseline characteristics between the two groups. However, at the 24-month follow-up, the Semaglutide-treated group exhibited significantly lower values for BMI, ASMI, handgrip strength, and gait speed compared to the control group (p< 0.05). Detailed results are presented in Table 2.

Table 1 Baseline Characteristics of Semaglutide-Treated Patients

Table 2 Comparison of Anthropometric and Muscle Parameters Between Semaglutide-Treated and Control Patients

Longitudinal Changes in Anthropometric and Muscle Parameters

Weight and Muscle Mass Dynamics

All subjects treated with Semaglutide showed a continuous reduction in BMI throughout the study period (p<0.001). A non-significant downward trend in ASMI emerged at 6 months, with significant reductions observed from month 12 onward. Cumulative ASMI loss reached 0.39 kg/m² in females and 0.26 kg/m² in males by study end. While the control group also showed sustained ASMI decline, the magnitude was markedly smaller than in the treatment group (Figure 1).

Figure 1 Longitudinal changes in BMI and muscle parameters during the study period. (a) BMI trajectories. (b) AMSI changes. (c) Handgrip strength variations. (d) Gait speed dynamics. Compare of Semaglutide group: male #<0.05, ##<0.01, ###<0.001; female #<0.05, ##<0.01, ###<0.001. Compare of control group: male *<0.05, **<0.01, ***<0.001; female *<0.05, **<0.01, ***<0.001.

Muscle Strength Trajectories

Handgrip strength: Males displayed a transient improvement at 6 months, followed by a progressive decline. Female participants, while showing no statistically significant change at 6 months, exhibited an upward trend that was subsequently followed by significant deterioration. Gait speed: Both genders exhibited similar patterns, with non-significant declines in intermediate phases but statistically significant overall reductions. Refer to Figure 2 for more information. Semaglutide-treated patients showed significantly greater reductions in ASMI, handgrip strength and gait speed compared to controls (see Table 2).

Figure 2 Multivariable regression analysis of predictors for muscle mass loss following semaglutide treatment. Semaglutide dosage, ASMI, and Gait speed were significant influences. Muscle mass loss (kg/m2) =1.536 + 0.096 × Semaglutide dosage ‒ 0.076 × ASMI + 0.004 × Hand grip strength ‒ 0.892 × Gait speed (R2=0.337).

Influential Factors of Semaglutide-Associated Muscle Loss

To identify determinants of muscle loss, we performed correlation analysis followed by multiple linear regression. The initial correlation analysis revealed that gender, age, baseline body mass index, diabetes duration, and chronic comorbidities showed no significant association with muscle mass loss. However, significant correlations were found with Semaglutide dosage, baseline ASMI, handgrip strength, and gait speed. As shown in Table 3.

Table 3 Correlation Analysis of the Variables with Muscle Loss

Subsequent multiple linear regression analysis, using muscle mass loss as the dependent variable and Semaglutide dosage, baseline ASMI, handgrip strength, and gait speed as independent variables, confirmed independent associations for semaglutide dosage, baseline ASMI, and gait speed, whereas handgrip strength lost statistical significance. The regression model (R² = 0.337) predicted muscle mass loss as: Muscle mass loss (kg/m²) =1.536+0.096×Semaglutide dosage-0.076× ASMI+0.004×Hand grip strength-0.892×Gait speed, R²=0.337. As displayed in Figure 2.

Discussion

Sarcopenia is an age-related condition characterized by the progressive loss of skeletal muscle mass and strength. It typically begins after the age of 30, at a rate of 0.1% to 0.5% annually, and accelerates beyond the age of 65 due to physiological and metabolic changes in aging populations.⁸ In this study, we investigated the effects of Semaglutide on muscle health in elderly patients with T2DM. Our analysis reveals that while Semaglutide effectively reduces body weight in elderly T2DM patients, it paradoxically accelerates this physiological muscle decline, particularly at higher doses and in individuals with pre-existing low muscle mass and function.

The weight-loss effects of Semaglutide, a long-acting GLP-1RA, are well-established,⁹ and this was confirmed in our elderly cohort. This weight loss may be linked to its ability to suppress appetite, delay gastric emptying, and regulate satiety signaling in the central nervous system.¹⁰ In older patients with T2DM, weight loss not only improves glycemic control but also reduces the risk of cardiovascular disease,¹¹ which is especially important in this population. However, despite the metabolic benefits of weight loss, it is crucial to consider the components of that weight loss. Our study found that weight loss was accompanied by a reduction in muscle mass and a decline in muscle function, which could negatively affect the long-term health of elderly patients. This finding contrasts with results from previous studies,¹² possibly because our follow-up population consisted entirely of elderly individuals. Skeletal muscle is the largest organ system in adults, accounting for approximately 30–45% of body weight in young adults, and it plays a vital role in protein homeostasis, as it contains the largest amount of body protein. Maintaining protein homeostasis, or net protein balance, is essential for muscle health. Under certain conditions, such as prolonged fasting, starvation, or inadequate protein intake, skeletal muscle can break down its proteins to mobilize amino acids.¹³ Semaglutide reduces body weight by suppressing appetite and decreasing energy intake; this diminished protein intake may lead to the body breaking down muscle proteins to provide necessary amino acids.¹⁰ Thus, using Semaglutide in older patients with T2DM may exacerbate the development of sarcopenia due to negative energy balance. Moreover, high doses of Semaglutide may more robustly suppress appetite and energy intake,¹⁴ leading to exacerbated muscle mass loss. The precise molecular mechanisms underlying this phenomenon require further investigation. These findings prompt critical inquiry into whether targeted protein supplementation may attenuate these effects in older populations – a promising avenue for future investigation.

Interestingly, we observed that Semaglutide initially improved muscle function, although in female participants this improvement only manifested as an upward trend. This effect may be mediated through the reduction of intramuscular fat infiltration, which is characteristically elevated in obese individuals. The accumulation of lipids and their metabolic byproducts within and between muscle cells can lead to mitochondrial dysfunction and subsequent declines in muscle strength and function.¹⁵ Previous studies have confirmed that GLP-1RA treatment significantly reduces this pathological fat infiltration.¹⁶ However, our data demonstrate that long-term administration results in gradual muscle mass loss, ultimately attenuating the initial functional improvements.

Our regression analysis identified baseline ASMI and gait speed as independent predictors of muscle loss, without significant gender or age differences. This suggests that reduced physical activity, resulting from declining muscle function, may create a vicious cycle of further muscle deterioration.¹⁷ Current research has shown that physical activity, particularly resistance training, has therapeutic effects on sarcopenia.¹⁸ Whether muscle loss can be prevented in Semaglutide users by increasing exercise participation needs further investigation.

The findings of this study have significant implications for clinical practice. While Semaglutide has notable benefits in improving glycemic control and promoting weight loss, its adverse effects on muscle mass should not be overlooked, especially in elderly patients. Clinicians should consider the following points when prescribing Semaglutide: (1) Patient selection: Carefully evaluate the risks and benefits of Semaglutide in elderly patients or those with pre-existing sarcopenia. (2) Dose adjustment: Start elderly patients on a low dose and gradually adjust according to their tolerance and response, avoiding high doses. (3) Monitoring and intervention: Regularly monitor muscle mass, physical function, and quality of life during Semaglutide treatment. This could be combined with moderate resistance training and optimized protein intake,¹⁹ if needed, to help slow muscle loss.

This study has several limitations. The relatively small sample size may limit the generalizability of the findings. While we accounted for major known confounders, we were unable to assess nutritional intake and physical activity patterns, which could influence muscle outcomes. Additionally, the observational nature of the study prevents causal conclusions. These limitations highlight the need for future prospective studies with standardized assessments of diet and exercise.

Conclusion

The use of Semaglutide is associated with muscle loss and functional decline in older adults with type 2 diabetes, particularly at higher doses. This effect is especially significant in patients with sarcopenia. Consequently, it is crucial to assess the risks and benefits for each elderly patient individually and to implement appropriate monitoring and interventions. The potential for nutritional supplementation and targeted exercise regimens to counteract semaglutide-associated muscle decline merits systematic investigation.

Data Sharing Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The study was approved by the Ethics Committee of Shijiazhuang People’s Hospital (Approval No: 2025075). All methods were performed by the Declaration of Helsinki, and the reporting followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Acknowledgments

We are grateful to all the patients who accepted to participate in this study.

Funding

There is no funding to report.

Disclosure

The authors declare that they have no competing interests in this work.

References

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Introduction

Somatic symptom disorder (SSD) refers to a psychiatric condition marked by an intense preoccupation with bodily symptoms.¹ These symptoms cause significant distress or disruption to daily life, evident through exaggerated and maladaptive cognitive, emotional, and behavioral reactions. For instance, an individual with SSD might exhibit chronic pain, gastrointestinal disturbances, or fatigue, alongside anxiety, catastrophizing thoughts, and avoidance behaviors.² Estimates of the prevalence of SSD in the general population range from 6.7% to 17.4%, with an average frequency of 12.9%.¹ Despite SSD’s elevated prevalence and strong association with detrimental functional consequences, such as diminished quality of life and increased healthcare utilization, research on interventions for its treatment and management remains sparse.³ As a result, healthcare providers continue to face challenges in providing adequate treatment for SSD.

Pharmacotherapy is one of the important approaches in the treatment of SSD. Pharmacological treatment for SSD includes non-psychotropic medications (such as β-blockers, non-steroidal anti-inflammatory drugs, and muscle relaxants for alleviating somatic symptoms), psychotropic medications, and herbal remedies (such as St. John’s wort). Psychotropic medications have been proven effective in treating some somatic symptoms, including selective serotonin reuptake inhibitors (SSRI) (eg, escitalopram, fluoxetine), serotonin and norepinephrine reuptake inhibitors (SNRI) (eg, venlafaxine), atypical antidepressants (eg, mirtazapine), and tricyclic antidepressants (eg, amitriptyline).⁴ However, a significant number of individuals suffering from SSD do not attain a treatment response, which is characterized by a reduction in severity exceeding 50%, following treatment with antidepressant monotherapy administered at adequate doses and for an adequate duration.⁵ Additionally, antidepressants mainly improve mood and relieve somatic symptoms by regulating neurotransmitters such as 5-hydroxytryptamine (5-HT) and norepinephrine.^5,6 However, patients with SSD may have more extensive neurotransmitter imbalances, including the dopamine (DA) system.⁷ Antipsychotic medications can regulate DA.⁸ Typical antipsychotic medications include chlorpromazine, trifluoperazine, and pimozide. These drugs, among the earliest developed in the field of antipsychotic medications, primarily exert their effects by targeting DA D2 receptors but may also interact with other receptors.⁹ In the 1990s, new antipsychotic medications are developed, known as second-generation or “atypical” antipsychotic medications, such as quetiapine, aripiprazole, and risperidone.¹⁰ Risperidone, classified as an atypical antipsychotic, exhibits robust antagonistic effects on DA D2, 5-HT2A, 5-HT2C, 5-HT1D, α1-, and α2-adrenergic receptors. It serves as an effective augmenting therapy for SSRI-resistant major depressive disorder. Furthermore, risperidone has the capability to counteract the SSRI-induced suppression of norepinephrine activity through its 5-HT2A antagonism.⁵ Paliperidone, which is the principal metabolite of risperidone, has demonstrated notable therapeutic benefits when used as an adjunctive treatment alongside citalopram in patients diagnosed with somatoform disorder.⁵ Compared with other second-generation antipsychotic medications, risperidone has relatively fewer adverse reactions.⁵ However, currently, antipsychotic medications are usually not used as monotherapy for SSD but are part of combination therapy, combined with other treatment methods to improve therapeutic efficacy.⁵

In recent years, the combined application of neuromodulation techniques and pharmacotherapy has provided new ideas for the treatment of SSD.¹¹ Repetitive transcranial magnetic stimulation (rTMS), a form of noninvasive brain stimulation, has the capability to modulate the neural excitability of specific brain regions, which has been applied in the treatment of various neurological and psychiatric disorders.¹² It has few side effects and is considered a promising intervention for improving symptoms in patients with SSD.¹³ rTMS has good efficacy in modulating targeted neural activity and further alleviating symptoms, so an increasing number of studies are focusing on examining the effects of rTMS on negative symptoms and cognitive deficits in patients with SSD.¹³ Xue Li et al report that rTMS combined with family intervention and risperidone has a synergistic effect in the treatment of schizophrenia, especially in improving positive symptoms, negative symptoms, and cognitive function.¹⁴ Additionally, data from Rui Li et al show that rTMS combined with risperidone treatment may affect the brain-gut-microbiota axis by regulating the gut microbiota in patients with chronic schizophrenia, thereby participating in the therapeutic effect.¹¹ Given this, this study aimed to explore the application effect of rTMS combined with low-dose antipsychotic medication (risperidone) in SSD.

It is worth noting that patients with SSD often have comorbid symptoms such as anxiety and depression and may have central nervous system dysfunction.^2,15 Neurotransmitter imbalance may be one of the mechanisms leading to symptoms and requires further study. It is well known that DA receptors are widely expressed in the body and function in both peripheral and central nervous systems.¹⁶ Their dysfunction is associated with anxiety and obsessive-compulsive symptoms.¹⁷ Furthermore, high levels of γ-aminobutyric acid (GABA) in the medial prefrontal cortex play an important pathophysiological role in the generation of somatic symptom disorders.¹⁸ Meanwhile, 5-HT abnormalities are also considered a key biological cause of somatic symptoms.⁵ On the other hand, data from Bumhee et al showed that patients with SSD have higher levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) compared with healthy controls, and hypersensitive C-reactive protein (hs-CRP) and IL-6 have a complete mediating inhibitory effect on the relationship between the functional connectivity strength of the default mode network and depression levels.¹⁹ Against this background, we included studies on neurotransmitters and inflammatory markers to comprehensively evaluate the biological effects of rTMS combined with risperidone on SSD. By analyzing changes in neurotransmitters such as DA, GABA, 5-HT, and inflammatory markers, we can reveal the potential mechanisms of combination therapy and provide a scientific basis for the treatment of SSD.

Materials and Methods

Ethics Statement

All experimental procedures were approved by the Medical Ethics Committee of The First Affiliated Hospital of Harbin Medical University, and patients or their families provided informed consent and signed an informed consent form. This study adhered to the Declaration of Helsinki.

Subjects and Grouping

Ninety patients with SSD admitted to The First Affiliated Hospital of Harbin Medical University from May 2023 to May 2024 were selected as the study subjects. Inclusion criteria: Patients who met the diagnostic criteria for SSD in the International Classification of Diseases, 10th Edition²⁰ and the Chinese Classification and Diagnostic Criteria for Mental Disorders, 3rd Edition, and had a Patient Health Questionnaire-15 score ≥ 5; patients aged 18–75 years; patients who had not received antipsychotic medication or rTMS within the past 6 months; patients on the 17-Item Hamilton Rating Scale for Depression (HAMD)²¹ score ≥ 17 points before treatment. Exclusion criteria: Patients with severe physical diseases (including stroke, malignant tumors, chronic obstructive pulmonary disease, end-stage renal disease, liver cirrhosis, myocardial infarction, etc) or brain organic diseases; patients with a history of schizophrenia, mania, and depression associated with various types of organic lesions; patients with epilepsy, acute-phase cerebrovascular accidents, intracranial infections, and intracranial presence of metal or other foreign bodies; patients with suicidal behavior or suicidal ideation; patients with allergies or sensitivities to all the medications used in the study; and women who were pregnant or breastfeeding.

Depending on the treatment regimen, the enrolled patients were divided into the medication and combination groups, with 45 cases each. The medication group was treated with low-dose antipsychotic medication, while the combination group received low-dose antipsychotic medication combined with rTMS.

Treatments

Patients in the medication group were treated with low-dose antipsychotic medication, specifically risperidone (Janssen Pharmaceutical Co., Ltd., Xi ‘an, China; State Drug Administration H20010309), administered orally at an initial dose of 0.5 mg twice daily, with the dose adjustable to 1.5 mg within one week, for a treatment cycle of 8 weeks. The combination group received low-dose antipsychotic medication combined with rTMS. Specific methods: The antipsychotic medication regimen was identical to that of the medication group. YRDCCY-1 transcranial magnetic stimulator (Yi Ruide Medical Equipment New Technology Co., Ltd., Wuhan, China) was used for the treatment, with an output pulse frequency range of 0–100 Hz and a peak stimulation intensity range of 1.5–6 Tesla. Specific operations: The patient was laid on the magnetic therapy bed, relaxed systemically, with the “8”-shaped coil placed on the right dorsolateral prefrontal cortex. The treatment was stimulated with an intensity of 1Hz frequency and 80% motor threshold, delivering 800 pulses per session, lasting 20 minutes per session, once daily for 5 consecutive days, followed by a 2-day break. This cycle was continued for 8 weeks.

Observation Parameters

General data: General demographic information such as gender, age, years of education, ethnicity, marital occupation, and place of residence of the study subjects were collected through a retrospective case system.

Anxiety and depression: The Hamilton Anxiety Rating Scale (HAMA)²² was used to assess patients’ psychological states. The scale includes 14 items, such as anxious mood, fear, and cognitive function, scored on a 0–4 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe), with a maximum score of 56. The HAMD-17 scale was used to assess the depressive symptoms in both groups of patients. This scale consists of 17 items covering aspects such as depressed mood, guilt, and suicidal thoughts, and is divided into five factors: anxiety somatization, weight, cognitive disturbance, retardation, and sleep disturbances. Each question has a different scoring standard, and the corresponding score is selected based on the patient’s response. The total score is then calculated.

Clinical efficacy: HAMD-17 was utilized to evaluate the treatment response. A reduction rate of ≥ 75% before and after treatment was considered clinical remission, 25–74% was considered effective, and < 25% was considered ineffective. The total effective rate was calculated as [(number of clinical remissions + effective cases) / total number of cases × 100%]. The reduction rate was calculated as [(pre-treatment HAMD-17 score – post-treatment HAMD-17 score) / pre-treatment HAMD-17 score × 100%].

Quality of life: The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) (SF-36)²³ was used for assessment. The survey included four functional domains: physical, social, psychological, and daily living. Each domain is scored out of 100, with higher scores indicating better quality of life for the patient.

Adverse reactions: The occurrence of adverse reactions including fatigue, drowsiness, anorexia, nausea, xerostomia, and dizziness, were compared.

Neurotransmitters levels: Before treatment (admission day 2) and after treatment (8 weeks of treatment), 5 mL of cubital vein blood was collected with an EDTA blood collection tube. Blood samples should be processed within 2 hours; otherwise, they must be stored at −80°C, with strict avoidance of multiple freeze–thaw cycles. The levels of GABA, 5-HT, and DA were measured using the enzyme-linked immunosorbent assay (ELISA).²⁴ ELISA kits for GABA (CB10292-Hu), 5-HT (CB10030-Hu), and DA (CB10524-Hu) were purchased from Coibo Biotechnology (Shanghai, China).

Inflammatory factor levels: Levels of CRP, IL-1β, and IL-10 were measured using ELISA. ELISA kits for CRP (CB10116-Hu), IL-1β (CB10347-Hu), and IL-10 (CB13566-Hu) were available from Coibo.

Statistical Processing

Data were processed using SPSS 26.0 software. The normality of measurement data was tested using the Shapiro–Wilk method, and all data conformed to a normal distribution. Additionally, the measurement data were expressed as mean ± standard deviation (Mean ± SD). Comparisons between groups used independent sample t-tests, and within-group comparisons used paired sample t-tests. Numeration data were expressed as [number of cases (n)], and analyzed using chi-square tests, with Yates’ correction applied to small sample sizes. A P-value < 0.05 was considered statistically significant.

Results

General Data

Baseline data differences between the two groups were analyzed, revealing no statistically significant differences in age, gender, disease duration, marital status, ethnicity, residence, or education level (P > 0.05), indicating comparability (Table 1).

Table 1 Comparison of General Data in the Two Groups

HAMA and HAMD Scores

There was no notable difference in HAMA and HAMD scores between the two groups before treatment (P > 0.05). After treatment, HAMA and HAMD scores in both groups decreased compared to pre-treatment levels (P < 0.05). Post-treatment improvements in HAMA and HAMD scores were better in the combination group than in the medication group (Table 2).

Table 2 Comparison of HAMA and HAMD Scores Before and After Treatment in the Two Groups

SF-36 Scores

There was no significant difference in SF-36 scores between the two groups before treatment (P > 0.05). After treatment, SF-36 dimension scores in both groups increased (P < 0.05), with the combination group’s scores higher than the control group’s (P < 0.05) (Table 3).

Table 3 Comparison of SF-36 Scores Before and After Treatment Between the Two Groups

Clinical Efficacy

The total effective rate in the medication group was 84.44% (38/45), while the total effective rate in the combination group was 97.78% (44/45). According to the chi-square test, the total effective rate in the combination group was higher than that in the medication group (P = 0.026) (Table 4).

Table 4 Comparison of Clinical Efficacy Between the Two Groups

Occurrence of Adverse Reactions

The medication group and the combination group showed no significant difference in the incidence of adverse reactions such as fatigue, drowsiness, anorexia, xerostomia, nausea, and dizziness (all P > 0.05) (Table 5).

Table 5 Comparison of the Incidence of Adverse Reactions Between the Two Groups

Neurotransmitters Levels

There was no significant difference in GABA, 5-HT, and DA levels between the two groups before treatment (P > 0.05). After treatment, GABA and 5-HT levels in both groups increased compared to pre-treatment levels, while DA levels decreased, with the combination group’s levels higher/lower than the medication group’s (Table 6).

Table 6 Comparison of Neurotransmitters Levels Between the Two Groups Before and After Treatment

Inflammatory Factor Levels

There was no remarkable difference between the pre-treatment levels of CRP, IL-1β, and IL-10 between the two groups (P > 0.05). After treatment, CRP and IL-1β levels in both groups decreased compared to pre-treatment levels, while IL-10 levels increased, with the combination group’s levels lower/higher than the medication group’s (Table 7).

Table 7 Comparison of Inflammatory Factor Levels Between the Two Groups Before and After Treatment

Discussion

SSD is common in primary health care institutions, and diagnosis and treatment are often challenging.¹ Therefore, this study evaluated the therapeutic effects of rTMS combined with low-dose antipsychotic medication in patients with SSD. The results showed that rTMS combined with low-dose antipsychotic medication has significant advantages in improving anxiety and depression, enhancing quality of life, and regulating neurotransmitter levels, and inflammatory factors in the treatment of SSD.

Specifically, the improvement in HAMA and HAMD scores in the combination group was better than that in the medication group, indicating that rTMS combined with low-dose antipsychotic medication is more effective in improving anxiety and depressive symptoms. Additionally, the SF-36 scores in the combination group were higher than those in the medication group, indicating that combination therapy is more effective in improving quality of life. Meanwhile, the total effective rate in the combination group was higher than that in the medication group, and there was no significant difference in the incidence of adverse reactions between the two groups, revealing that rTMS combined with low-dose antipsychotic medication is superior to monotherapy in overall efficacy and does not increase the risk of adverse reactions. Studies have reported that rTMS leads to a greater reduction in depressive symptoms than medication, which is further reflected in higher rates of response and remission. Additionally, rTMS results in a more substantial decrease in anxiety and anhedonia symptoms compared to switching antidepressants.²⁵ Furthermore, in the study of Ren et al, intermittent theta burst-rTMS (iTBS-rTMS) demonstrates a favorable therapeutic effect in patients with methamphetamine use disorder, with improvements in both depression and impulsivity. These enhancements are strongly associated with the therapeutic efficacy of iTBS-rTMS.²⁶

In addition, this study highlighted that the levels of GABA and 5-HT in the combination group were higher than those in the medication group, and the level of DA was lower than that in the medication group, indicating that rTMS combined with low-dose antipsychotic medication is more effective in regulating neurotransmitter levels. According to previous results, the serum levels of 5-HT in both the acupuncture + rTMS combination group and the rTMS-only group are found to be higher post-treatment compared to their pre-treatment levels.²⁷ In the study by Feng et al, after rTMS treatment, the GABA levels are notably elevated.²⁸ A study reveals that antipsychotic medications such as risperidone may regulate N-methyl-D-aspartate receptors through the glycogen synthase kinase 3β-β-catenin signaling pathway and/or the activation of cyclic adenosine monophosphate response element-binding protein 1, and the regulation of GABAₐR may also be related to these signaling pathways.²⁹ Thomas et al’s study shows that risperidone affects motor activity and neural activity in mice, especially having a significant impact on neural oscillations in the prefrontal cortex and hippocampus, by blocking DA receptor D₂R and regulating the activity of serotonin receptors (5-HT₁AR and 5-HT₂AR).³⁰ Based on the results of this study, there is a synergistic mechanism in neurotransmitter regulation when risperidone is combined with rTMS. Risperidone, as a D2 receptor antagonist, can block excessive DA activity in the mesolimbic system to alleviate positive symptoms,¹⁴ while rTMS activates glutamatergic neurons in the prefrontal cortex through high-frequency stimulation, promoting DA release and enhancing prefrontal-striatal circuit function. The combined treatment may partially counteract the inhibitory effect of risperidone on DA, thereby optimizing DA metabolic balance. Additionally, risperidone indirectly increases synaptic 5-HT levels by blocking 5-HT2A receptors, and rTMS stimulates the dorsolateral prefrontal cortex to increase 5-HT release into the limbic system. The synergy of the two may increase 5-HT concentrations in relevant brain regions, thereby improving anxiety and depressive symptoms. On the other hand, rTMS can enhance GABAergic interneuron activity to inhibit prefrontal cortex hyperactivity, and risperidone can indirectly regulate DA-GABA interactions to enhance GABAergic inhibition. The combined treatment can more effectively reduce prefrontal cortex excitability and reduce anxiety and obsessive-compulsive symptoms.

Meanwhile, this study also observed that the levels of CRP and IL-1β in the combination group were lower than those in the medication group, and the level of IL-10 was higher than that in the medication group, indicating that rTMS combined with low-dose antipsychotic medication is more effective in regulating inflammatory marker levels. In line with the results of the present study, in the study of Yang et al, deep rTMS reduced microglial activation at the lesion sites and normalized cytokine levels (IL-1β, IL-6, and IL-10) in regions affected by cuprizone.³¹ Based on the results of this study, rTMS may activate the vagus nerve-cholinergic anti-inflammatory pathway, inhibit microglial activation, and reduce the release of pro-inflammatory cytokines (such as IL-1β). Although risperidone does not directly have anti-inflammatory effects, it may inhibit microglial M1 polarization by regulating the DA signaling pathway. When combined, the two may synergistically reduce peripheral blood CRP and IL-1β levels and increase the level of the anti-inflammatory cytokine IL-10.

Limitation

This study preliminarily revealed the efficacy of rTMS combined with risperidone in the treatment of SSD in improving anxiety and depression, enhancing quality of life, regulating neurotransmitter levels, and inflammatory factors. However, this study also has some limitations. For example, we did not perform sample size calculation, and the sample size was small, which may affect the generalizability of the findings. Additionally, the 8-week observation period in this study may not be sufficient to assess the long-term efficacy and potential delayed effects of rTMS combined with risperidone treatment. The lack of long-term follow-up may not allow for the assessment of symptom recurrence rates and drug dependence after treatment.

Conclusion

In conclusion, this study confirms that rTMS combined with low-dose antipsychotic medication is superior to monotherapy in improving anxiety and depression, enhancing the quality of life, regulating neurotransmitter levels, and inflammatory factors in the treatment of somatic symptom disorder, with fewer side effects and significant clinical efficacy. This study provides a new direction for the treatment of SSD, and it is hoped that the treatment regimen can be further optimized to benefit more patients in the future. Importantly, future research should further verify the mechanisms and long-term safety of combination therapy by expanding the sample size, extending the follow-up period, and controlling confounding factors (such as treatment adherence, social support systems, etc). Additionally, the treatment of SSD requires multidisciplinary collaboration, including psychiatry, neurology, and psychology. The multidisciplinary collaborative treatment model can integrate the advantageous resources of various disciplines to provide patients with more personalized and comprehensive treatment plans and improve the overall treatment level of SSD.

Ethical Statement

All experimental procedures were approved by the Medical Ethics Committee of The First Affiliated Hospital of Harbin Medical University, and informed consent was signed by patients’ families.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Funding

No funds, grants, or other support was received.

Disclosure

The authors declare that they have no conflicts of interest for this work.

References

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Introduction

The prevalence of diabetes, particularly type 2 diabetes (T2D), is rising globally, posing a significant public health challenge due to its various acute and chronic complications.¹ Among these complications, cardiovascular diseases (CVDs) stand out as the leading cause of death in patients with T2D.² Vascular dysfunctions, including arterial stiffness (AS) and impaired vasodilation, can emerge before the onset of severe CVDs symptoms.³ Therefore, early assessment of AS is particularly important in the management of T2D. The brachial-ankle pulse wave velocity (baPWV) is a simple, effective and non-invasive method for evaluating AS,⁴ and can independently predict cardiovascular risk, providing important evidence for assessing the development of CVDs in individuals.⁵

Insulin resistance (IR) is considered a significant factor to AS and the progression of CVDs.⁶ While the euglycemic hyperinsulinemic clamp (EHC) is considered the gold standard for assessing IR,⁷ its invasive nature, time consuming and requirement for hospitalization limit its practical applicability. The homeostasis model assessment index (HOMA-IR) offers a simpler approach to assessing IR.⁸ However, it presents specific challenges for patients undergoing insulin therapy. Recently, a growing number of non-insulin-based IR surrogate markers have been proposed, including the triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-c) ratio, and metabolic score for insulin resistance (METS-IR).^9–11 These markers have been associated with various metabolic diseases. One of our previous studies examined their relationship with nonalcoholic fatty liver disease (NAFLD) in patients with T2D, highlighting their clinical relevance in this context.¹² Building on this foundation, our current study shifts the focus toward AS, a distinct yet critical cardiovascular complication in T2D. A more recent development is the natural log transformation of the glucose disposal rate (log_e GDR), a non-insulin-based model to assess insulin sensitivity (IS) in T2D patients.¹³ The log_e GDR is calculated based on body mass index (BMI), triglycerides (TG), the urinary albumin to creatinine ratio (UACR) and γ-glutamyl transferase (GGT), and it has been validated and demonstrated a strong association with CVDs and mortality rates.¹³ Despite these advances, no studies to date have specifically investigated the relationship between the log_e GDR and AS in T2D. Based on the groundwork laid by our earlier research, this study aims to explore the novel association between log_e GDR and AS, offering fresh insights into the complex interplay between IS and vascular health.

The prevalence of non-obese T2D is gradually increasing, particularly in Asian countries.^14,15 Although CVDs and other conditions have traditionally been associated with obesity and being overweight, recent evidence suggests that non-obese T2D patients may have higher all-cause and cardiovascular mortality rates.^16,17 This could be attributed to factors such as increased visceral fat, impaired IS, and heightened inflammatory responses despite a normal BMI.¹⁸ Furthermore, recent studies have reported non-obese T2D patients have a comparable or even higher prevalence of AS compared to their obese counterparts¹⁸ Due to significant differences in metabolic characteristics between obese and non-obese diabetic patients, particularly regarding IS.¹⁹ And research exploring the relationship between IR surrogate markers and AS in non-obese patients with T2D remains limited. Therefore, we aim to analyze the relationship between the log_e GDR and AS in this population.

Methods

Study Design and Population

We retrospectively reviewed the medical records of patients aged ≥ 18 years with T2D from the Department Endocrinology of Linyi People’s Hospital, from January 2020 to March 2023. The exclusion criteria were (1) subjects missing key anthropometric measurements (height and weight); (2) subjects who had severe liver and kidney dysfunctions; (3) subjects with a history of angina, myocardial infarction and cerebrovascular accident; (4) subjects who had not undergone the baPWV tests or whose clinical data were incomplete, including GGT, TG and UACR; (5) subjects with BMI ≥ 24 kg/m². Ultimately, a total of 790 non-obese patients with T2D were eventually included (Figure 1).

Figure 1 The flow chart of study participants selection.

It is important to note that a portion of the participants included in the current study were also part of our previous work, which primarily investigated the association between IR markers and NAFLD in the overall T2D population. In terms of exclusion criteria, the previous study mainly excluded confounding factors that could affect the diagnosis and analysis of fatty liver disease.¹² For the overlapping populations, we further compared differences in baseline characteristics and various IR indices between the two studies, and the results did not show significant differences, suggesting that the results of this study are relatively stable and have some replication.

Demographic Information

The sex, age, diabetes duration and self-reported current cigarette smoking and drinking status were collected.

Physical Examinations

According to unified standards, the height, weight, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured and collected. The bioelectrical impedance analysis (Omron DUALSCAN HDS-2000, Kyoto, Japan) was used to measure the visceral fat area (VFA) and subcutaneous fat area (SFA).

Each participant’s baPWV was measured using the automated system BP-203RPE III (Omron Healthcare Co., Japan) by trained technicians. The device simultaneously recorded pulse waveforms from the brachial and tibial arteries and automatically calculated baPWV values. Before measurement, participants were required to rest in a supine position for at least 5 minutes to ensure hemodynamic stability. Subsequently, appropriately sized cuffs were placed on both upper arms and ankles, and the device was operated according to standard protocols to obtain waveform signals and compute baPWV values.²⁰ To enhance measurement accuracy, this study analyzed data in cases where there was a significant difference between left and right baPWV values and assessed each side’s baPWV separately. AS was defined as baPWV ≥1800 cm/s.

Laboratory Measurements

Following an overnight fast, blood samples were collected and analyzed in the morning for alanine aminotransferase (ALT), aspartate aminotransferase (AST), GGT, TG, HDL-c, total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c), serum creatinine (Scr), uric acid (UA), Cystatin C (Cys C), hemoglobin (Hb), fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c), fasting insulin (FINS) and UACR. A comprehensive overview of the tools and methods utilized in this research is available in our earlier publication.¹² Non-obese was defined as BMI < 24 kg/m².

Parameter Calculation

1. BMI = weight (kg) / height² (m²);
2. eGFR = 175 * Scr (mg/dL) ^−1.234 * age ^−0.179 * (0.79, if female);²¹
3. HOMA-IR = FBG (mmol/L) * FINS (µU/mL)/22.5;⁸
4. TyG index = ln [TG (mg/dL) × FBG (mg/dL)/2];¹⁰
5. TG/HDL-c ratio = TG (mmol/L)/HDL-c (mmol/L);¹¹
6. METS-IR = ln [(2*FBG (mg/dL)) + TG (mg/dL)] *BMI)/(Ln [HDL-c (mg/dL)]);⁹
7. Log_e GDR = 5.3505–0.3697 * log_e (GGT, IU/L) – 0.2591 * log_e (TG, mg/dL) – 0.1169 * log_e (UACR, mg/g) – (0.0279*BMI, kg/m²).¹³

Statistical Analysis

Statistical analysis was performed using SPSS 26.0 (SPSS Inc, Chicago, USA) and R (version 4.3.2). Data were presented as means ± SD for normally distributed variables and as medians (interquartile ranges) for non-normally distributed variables. Independent-Samples T test and Mann–Whitney U-test were used for comparisons of normally and abnormally distributed continuous variables between two groups, respectively. Categorical variables were presented as percentage (%) and were compared by Chi-square test. For normally distributed data, an Analysis of Variance (ANOVA) and Student-Newman-Keuls tests were used for multiple and pairwise comparisons between the log_e GDR tertiles groups, while the Kruskal–Wallis one-way ANOVA test was used for abnormally distributed data. Pearson correlation and multiple linear stepwise regression analyses were used to evaluate the independent correlations of baPWV. Univariate logistic regression analysis and directed acyclic graphs (DAG) were used to guide the selection of covariates for AS. The DAG was constructed using the dagitty package. And the identified minimal adjustment set includes age, BMI, diabetes duration, FBG, TG, HOMA-IR, METS-IR, TG/HDL-c ratio and TyG index. Logistic regression analysis was used to analyze the independent correlates of AS. Net reclassification improvement (NRI) analysis was performed using the survIDINRI package in R to assess the incremental predictive value of log_e GDR compared with other IR markers for identifying AS. Statistical differences were defined by P-value (two-tailed) less than 0.05.

Results

Clinical and Biochemical Characteristics

The clinical and biochemical characteristics of the participants are shown in Table 1. A total of 790 non-obese patients with T2D were enrolled in our study. The subjects were divided into two groups including non-AS group (baPWV < 1800cm/s) and AS group (baPWV ≥ 1800cm/s). Compared with the non-AS group, the age, diabetes duration, VFA, SFA, SBP, DBP, AST, GGT, UA, Scr, UACR and Cys C were increased in AS group, but the HbA1c, eGFR, Hb and log_e GDR were markedly reduced (all P < 0.05). There were no obvious differences in BMI, TC, LDL-c, HDL-c, TG, FBG, FINS, ALT, HOMA-IR, TG/HDL-c ratio, TyG index, METS-IR and the percentages of males, smoking and drinking between the two groups (all P > 0.05).

Table 1 Clinical and Biochemical Characteristics by Presence of AS

Then, according to tertiles of log_e GDR, the participants were divided into three groups: T1 (0.25–1.98), T2 (1.98–2.28) and T3 (2.28–3.12) (Table 2). As the log_e GDR tertiles increased, the age, diabetes duration, BMI, VFA, SFA, SBP, DBP, TC, LDL-c, TG, FINS, HbA1c, ALT, AST, GGT, UA, Scr, UACR, Cys C, HOMA-IR, TyG index, TG/HDL-c ratio, METS-IR, baPWV, the percentages of smoking, drinking and AS were gradually decreased, while the HDL-c, Hb and eGFR were gradually elevated (all P < 0.05). The FBG and the percentages of males were no significant different between the three groups (both P > 0.05).

Table 2 Comparison of Variables According to the Tertiles of Loge GDR

Correlation Between baPWV or AS and Each Variable by Univariate Analysis

As shown in Table 3, a Pearson correlation analysis was performed to analyze the association between baPWV and each variable. The results displayed that the baPWV was positively related to age, diabetes duration, VFA, SFA, SBP, DBP, TG, FINS, GGT, UA, UACR, Cys C and TG/HDL-c ratio, while negatively to the Hb, HbA1c, eGFR and log_e GDR (all P < 0.05). BMI, TC, LDL-c, HDL-c, FBG, ALT, AST, HOMA-IR, TyG index and METS-IR were not correlated with baPWV (all P > 0.05).

Table 3 The Correlation Between baPWV or AS and Different Variables by Univariate Analysis

Moreover, univariate regression analysis was conducted to identify the factors associated with AS. The results showed that AS was positively related to the age, diabetes duration, VFA, SFA, SBP, DBP, FINS, AST, UA, UACR, Cys C, and negatively to the Hb, HbA1c, eGFR and log_e GDR (all P < 0.05). No significant relationships existed between AS and BMI, TC, LDL-c, TG, HDL-c, FBG, ALT, GGT, HOMA-IR, TyG index, TG/HDL-c ratio, METS-IR and the percentages of males, smoking and drinking (all P > 0.05).

Independent Variables of baPWV by Multiple Linear Stepwise Regression Analysis

The covariates for multivariate linear regression analysis were determined based on the results of Pearson correlation analysis and previous literature reports. A multiple linear stepwise regression analysis was conducted to analyze the independent correlations of baPWV (Table 4). The age, diabetes duration, VFA, SFA, SBP, DBP, TG, FINS, GGT, UA, UACR, Cys C, TG/HDL-c ratio, Hb, HbA1c, eGFR and log_e GDR were set as the dependent variables based on the results of Pearson correlation analysis, and the results displayed that the age, SBP and log_e GDR fit a regression model (all P < 0.05).

Table 4 Multivariate Linear Regression Analysis with baPWV as the Dependent Variable

Independent Correlations of AS by Logistic Regression Analysis

Finally, AS was served as the dependent variable, and based on the results of univariate logistic regression analysis, the DAG diagram (Figure 2), and previous literature, the following variables were included as independent variables: age, diabetes duration, VFA, SFA, SBP, DBP, FINS, HbA1c, AST, UA, eGFR, UACR, Cys C, Hb, BMI, FBG, TG, HOMA-IR, TG/HDL-c ratio, TyG index, METS-IR, log_e GDR and the percentages of smoking and drinking. A logistic regression analysis was performed to analyze the independent correlates of AS (Table 5), and the results found that after adjusting for the other variables, the log_e GDR (OR: 0.286, 95.0% CI for OR: 0.110–0.743), age (OR: 1.196, 95.0% CI for OR: 1.138–1.258), SBP (OR: 1.053, 95.0% CI for OR: 1.031–1.075) and FBG (OR: 0.886, 95.0% CI for OR: 0.792–0.990) were independently related to AS.

Table 5 The Independent Variables for AS

Figure 2 The DAG of identifying confounding variables.

Predictive Value of IR Markers for AS

To assess the incremental predictive value of various IR markers for AS, NRI analysis was performed based on logistic regression models (Table 6). All models were adjusted for potential confounders, including age, diabetes duration, VFA, SFA, SBP, DBP, FINS, HbA1c, AST, UA, eGFR, UACR, Cys C, Hb, BMI, FBG, TG, smoking and drinking. Building upon the base model without any IR marker, integrating log_e GDR yielded a modest improvement in the model’s ability to reclassify patients with AS (NRI:0.043, 95% CI 0.009–0.079, P = 0.011). In contrast, building upon the base model, integrating other IR markers such as HOMA-IR (NRI:0.007, P = 0.697), TyG index (NRI:0.011, P = 0.356), TG/HDL-c ratio (NRI:0.006, P = 0.317), and METS-IR (NRI: −0.004, P = 0.568) did not significantly improve the predictive performance.

Table 6 Analysis of the NRI for Predicting AS

Discussion

This cross-sectional study of non-obese patients with T2D revealed a significant negative association between the log_e GDR and both baPWV and AS. Increased log_e GDR tertiles corresponded with a significant reduction in baPWV and AS incidence. Furthermore, after adjusting for confounding factors, the log_e GDR was independently associated with baPWV and AS.

IR is common among diabetic patients, leading to endothelial dysfunction and inflammatory responses that contribute to AS and atherosclerosis.²² Although the EHC is considered the gold standard for assessing IS, its complexity, time consuming, and requirement for specialized personnel limit its use in large-scale clinical studies. HOMA-IR is a commonly used and simpler indicator of IR, but it relies on FINS. Previous studies have shown that fluctuations in insulin levels can be significantly influenced by an individual’s glucose tolerance and the effects of treatment. Therefore, FINS levels may not be entirely accurate for patients with T2D undergoing treatment.^23,24 Recently, an increasing number of studies have explored the close association between non-insulin-based IR surrogate indicators and AS across various populations. For instance, a study in a healthy Japanese cohort found a significant correlation between the METS-IR and AS.²⁵ A study involving 1895 participants showed a close correlation between the TyG index and the TG/HDL-c ratio with AS in hypertensive patients, while no such relationship was observed in patients with prehypertension.²⁶ Furthermore, research on patients with T2D had indicated that the TyG index was independently and more strongly associated with the prevalence of increased AS compared to HOMA-IR.²⁰ The relationship between non-insulin-based IR surrogate indicators with AS had also been validated in lean postmenopausal women, Chinese non-hypertensive and older subjects.^27–29

The log_e GDR is a newly developed model for assessing IS in T2D, and it has been validated as a reliable EHC-based surrogate capable of capturing the variability of IS in patients with T2D well.¹³ The inclusion of metabolic components (GGT, UACR, BMI and TG) allows log_e GDR to reflect a more comprehensive metabolic profile and potentially capturing a broader range of pathogenic mechanisms. In our study, we found that it was closely associated with IR markers as well. As the tertiles of log_e GDR increased, significant reductions were observed in other IR markers, suggesting a consistent relationship between log_e GDR and IS. Notably, we found that the log_e GDR was independently related to baPWV and AS. This relationship remains important even after adjusting for other confounding factors including IR markers (HOMA-IR, TG/HDL-c ratio, TyG index, and METS-IR).

The mechanisms potentially linking log_e GDR to AS are likely multifactorial and may involve several key pathways. The components included in the calculation of log_e GDR, including GGT, UACR, BMI and TG, may have been suggested as part of circadian syndrome.³⁰ Recent studies indicate that circadian syndrome may be a better predictor of CVDs risk than metabolic syndrome,³⁰ suggesting that log_e GDR might reflect a disruption in circadian rhythms, potentially influencing cardiovascular health. GGT is a key marker of oxidative stress, promoting endothelial dysfunction by reducing nitric oxide bioavailability and increasing vascular inflammation, both of which contribute to arterial stiffening. TG facilitates lipid accumulation in the vascular wall, leading to foam cell formation and atherosclerosis progression. Elevated TG levels are also associated with increased production of small, dense LDL particles, which enhance oxidative stress and vascular inflammation. UACR reflects endothelial dysfunction and vascular damage, as albuminuria is linked to increased vascular permeability and low-grade inflammation, both contributing to arterial remodeling. Additionally, BMI, particularly in the context of visceral adiposity, is associated with chronic low-grade inflammation and activation of the renin-angiotensin-aldosterone system, further promoting vascular stiffness. These components effectively represent the key metabolic pathways leading to AS, supporting the close relationship between log_e GDR and AS.^31–33

Additionally, AS is a degenerative vascular process that increases with age.³⁴ High SBP levels may damage endothelial function, leading to progressively stiffer arteries.³⁵ Be consistent with the above findings, we found a strong relationship between age and SBP with AS in non-obese patients with T2D. This underscores the importance of managing SBP as a modifiable risk factor for AS, particularly in this population. Interestingly, we observed a negative correlation between AS and FBG, which was inconsistent with most studies that suggested elevated FBG was a significant risk factor for AS.³⁶ The multifaceted influencing factors of AS may help explain this phenomenon. As mentioned earlier, the average age in the AS group was significantly higher than that in the non-AS group, and some studies have suggested that older diabetic patients tend to have better blood glucose control.³⁷

The relationship between the novel IS index log_e GDR and AS has not been extensively studied in the context of non-obese T2D. Our study is the first to observe a strong association between log_e GDR and AS in non-obese patients with T2D, highlighting its potential clinical significance. Although non-obese individuals with T2D may have normal body weight, they can still exhibit significant vascular changes. Since log_e GDR incorporates metabolic parameters including BMI, TG, UACR and GGT, it may reflect a broader metabolic disorder amenable to intervention than other IR markers. Importantly, logₑ GDR demonstrated the highest NRI among the evaluated IR indicators, indicating relatively better discriminatory capacity for AS. However, the overall improvement in risk prediction was modest, suggesting that its incremental value in risk stratification may be limited. Therefore, while logₑ GDR shows potential as a complementary tool for early identification of cardiovascular risk in non-obese T2D patients, its clinical utility should be interpreted with caution. Further prospective studies with larger, diverse cohorts are needed to confirm these findings and to clarify the role of logₑ GDR in improving cardiovascular risk prediction models.

Several limitations of this study should be acknowledged. First, as with all cross-sectional studies, we cannot establish causality between log_e GDR and AS. Longitudinal studies are essential to determine the temporal relationship and causal pathways between these variables. Second, using BMI < 24 kg/m² to define “non-obese” may not perfectly capture individuals with increased visceral adiposity, which is a key driver of metabolic dysfunction. Future studies could consider including measures such as waist circumference or waist-to-hip ratio, which provide more direct insight into visceral fat distribution. Lastly, this study is single-center and based on a small sample size, which may limit the generalizability of the results. Future prospective multi-center studies involving larger populations are needed to confirm these findings and further investigate the underlying mechanisms.

Conclusion

In conclusion, the log_e GDR, as a new simple index of IS, is independently associated with AS in non-obese patients with T2D. Its inclusion in existing risk models modestly improved the identification of arterial stiffness. The potential utility of log_e GDR in cardiovascular risk assessment warrants further investigation and validation in future studies.

Ethics Approval and Consent to Participate

The study was approved by the Human Ethics Committee of the Linyi People’s Hospital. All procedures were performed in accordance with ethical standards laid out in the Declaration of Helsinki. Informed consent was obtained from the patients.

Acknowledgments

Shuwei Shi is currently Department of Endocrinology, Linyi People’s Hospital Affiliated to Shandong Second Medical University, Linyi, China. This study was conducted while she was affiliated with the School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China. Baolan Ji and Guanqi Gao are co-corresponding authors for this study.

Funding

This study was supported by grants from the Postdoctoral Program of Affiliated Hospital of Jining Medical University (JYFY322152).

Disclosure

All authors declare that they have no competing interests in this study.

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Introduction

The advancement of medical technology and evolving healthcare concepts has led to the widespread adoption of day surgery, a new medical service model.¹ Anaesthetic techniques are the cornerstone of day surgery. Therefore, improving anaesthesia concepts and methods is essential to ensure safe and effective outcomes in this setting.

In clinical practice, drugs with complementary effects are often used together. The combination of sedatives and opioids is a standard practice for procedural sedation and general anaesthesia. For example, the combination of propofol with fentanyl, midazolam with fentanyl, and propofol with remifentanil improved efficacy, reducing the dosage of both drugs, and reducing adverse effects.^2–5 However, drug interactions can alter pharmacological outcomes,⁶ making it essential to understand the characteristics of these interactions. Remimazolam, a novel, ultrafast, and short-acting benzodiazepine, gained approval for use in both procedural sedation and general anaesthesia.^7–9 Alfentanil, a fentanyl derivative, is a short-acting μ-opioid analgesic widely used in various clinical settings, including endoscopy, abortion, and general anaesthesia.^10–13

Given the rapid onset and offset of remimazolam and alfentanil, their combination could be an ideal anaesthetic regimen for day surgeries. Despite this potential, only a few studies have explored the remimazolam-alfentanil interaction. Our hypothesis is that alfentanil may enhance the sedative effects of remimazolam during anaesthesia induction in patients undergoing urological day surgery.

Methods

Study Design and Participants

This study was a single-centre, single-blinded, randomised clinical trial. Ethical approval was granted by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (identifier: 2022-KY-E-302; Chairperson: Prof. Songqing He) on 13 September 2022 and was registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn; registration number: ChiCTR2200064130, principal investigator: Xuehai Guan; date of registration: 27 September 2022). Written informed consent was obtained from all patients before enrolment. This trial was performed at the First Affiliated Hospital of Guangxi Medical University in accordance with the Declaration of Helsinki and CONSORT guidelines.

A total of 114 patients, aged 18–65 years, with an American Society of Anaesthesiologists (ASA)physical status I–III, undergoing elective urological day surgery under general anaesthesia, were enrolled. Patients with a history of difficult airway (modified Mallampati class 3–4), asthma, severe hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg), pulmonary heart disease, pulmonary arterial hypertension, cardiac insufficiency, hyperthyroidism, epilepsy, or psychosis were excluded. Further exclusion criteria included allergic reactions to drugs, obesity (body mass index, BMI ≥ 30 kg.m⁻²), pregnancy, and analgesic abuse.

Randomisation and Masking

Enrolled patients were randomly assigned to either the RMZ-AF or AF-RMZ group using a computer-generated randomisation code (EpiCalc 2000 software) in a 1:1 ratio. Randomisation was performed by an independent anaesthesiologist who was only involved in patient assignment and drug preparation. Group assignments were concealed in sealed envelopes. Patients, surgeons, and data collectors were blinded to the group allocation throughout the process, with the allocation only revealed after data collection and analysis were completed.

Anaesthesia Management and Intervention

All patients fasted for 8 h before surgery, with no premedication administered. Upon arrival in the operating room, standard monitoring was initiated, including non-invasive blood pressure measurement, electrocardiography, capnography, pulse oximetry (SpO₂), and bispectral index (BIS). All patients inhaled 100% oxygen through a mask for 3 min before anaesthesia induction. In the RMZ-AF group, anaesthesia was induced using remimazolam tosilate (RMZ; Jiangsu Hengrui Medicine Co., Lianyungang, China; diluted with normal saline to 1 mg mL⁻¹), starting at 6 mg kg⁻¹ h⁻¹ until the BIS reached 40–60 and was maintained between 0.2–2 mg kg⁻¹ h⁻¹. When BIS was within 40–60, alfentanil (AF; 30 µg kg⁻¹ IV; Yichang Humanwell Pharmaceutical Co., Yichang, China) and rocuronium (0.6 mg kg⁻¹ IV; Sinopharm Chemical Reagent Co., Shanghai, China) were administered. In the AF-RMZ group, anaesthesia was induced by using alfentanil (30µg kg⁻¹ IV), followed by remimazolam tosilate, starting at 6 mg kg⁻¹ h⁻¹ until BIS reached 40–60 and was maintained between 0.2–2 mg kg⁻¹ h⁻¹. When BIS was within 40–60, rocuronium (0.6 mg kg⁻¹ IV) was administered. In both groups, a laryngeal mask airway (LMA) was inserted 1 min after rocuronium administration. Anaesthesia was maintained using a combination of remimazolam (0.2–2 mg kg⁻¹ h⁻¹) and alfentanil (1–2 µg kg⁻¹ min⁻¹), adjusted based on the clinical signs and symptoms, BIS values (maintained at a range of 40–60), and the patient’s overall condition. Rocuronium was administered as a repeated bolus dose of 0.1–0.2 mg kg⁻¹ when needed. All patients underwent mechanical ventilation (tidal volume, 8 mL kg⁻¹; respiratory rate: 8–12 breaths min⁻¹; oxygen concentration, 60%; and fresh gas flow, 2 L min⁻¹). All patients with hypotension (a 30% decrease in mean arterial blood pressure (MBP) compared with baseline) were treated with ephedrine at the discretion of the attending anaesthesiologist.

If signs of intraoperative awakening (BIS > 60) were detected, the remimazolam infusion rate was adjusted to 10 mg kg⁻¹ h ⁻¹ for up to 1 min. If awakening signs persisted, remimazolam was discontinued and replaced with propofol. All drugs were discontinued at the end of the surgery, and patients were transferred to the post-anaesthesia care unit (PACU) for recovery.

Outcomes

The primary outcome was the time from remimazolam administration to loss of consciousness (LOC) during anaesthesia induction. The consciousness was assessed by using Modified Observer`s Assessment Alertness/Sedation Scale (MOAA/S; 0, no response after painful trapezius squeeze, defined as LOC; 1, responds only after painful trapezius squeeze; 2, responds only after mild prodding or shaking; 3, response to name spoken loudly and/or repeatedly; 4, response to name spoken in normal tone; 5, response readily to name spoken in normal tone) with 10s interval during anaesthesia induction.

Secondary outcomes included anaesthetic and surgical characteristics, vital signs, and adverse events. The durations of surgery, anaesthesia, and PACU stay, as well as the time of eyes-opening and extubation, were recorded. We recorded the administration of remimazolam and alfentanil at the following time points: from administration to LOC, at BIS ≤ 60, and at the end of surgery. Total administration of rocuronium, ephedrine, and crystalloid infusion volumes were also recorded. Vital signs (mean arterial blood pressure [MBP], heart rate, SpO₂, and BIS) were recorded at the following time points: 5 min before anaesthesia (baseline), at LOC, at BIS ≤ 60, at intubation, at 1 and 5 min after intubation, at the beginning of surgery, at 5 min after surgery, at time of eyes-opening, at time of extubation, and at discharge from the PACU. Adverse events such as hypertension (≥ 30% increase in MBP from baseline), hypotension (≥ 30% decrease in MBP from baseline), bradycardia (<50 beats min⁻¹), tachycardia (>100 beats min⁻¹), injection pain, dysphoria, nausea/vomiting, awareness, delirium, and hiccups were also recorded.

Statistical Analyses

Statistical analyses were performed using GraphPad Prism 9.0 (Dotmatics, Boston, MA, USA). The normality and equality of variances for continuous variables were tested using the Kolmogorov–Smirnov and sphericity tests, respectively. Continuous values with normal distribution and equal variance are presented as means (SD) and were analysed using an unpaired t-test or repeated-measures two-way analysis of variance (ANOVA), followed by Bonferroni’s multiple comparison test. Continuous values with non-normal distribution and unequal variance are presented as medians (interquartile range [IQR]) and were analysed using the Mann–Whitney U-test. Categorical values are presented as numbers (%) and were analysed using Fisher’s exact test. A P-value of <0.05 was considered statistically significant.

This study was designed as a superiority trial. PASS software (version 11.0; NCCS, Utah, USA) was used to calculate the sample size. Preliminary tests showed that the time from remimazolam administration to LOC (mean [SD]) was 106.0 (30.0) s and 123.0 (32) s in the AF-RMZ and RMZ-AF groups, respectively. We calculated that 54 patients per group were required to achieve 80% power at a two-sided alpha of 0.05 to detect a significant difference in the primary outcome. To account for a potential 5% dropout rate, we enrolled 57 patients in each group.

Results

Between September 2022 and December 2023, 171 patients were screened for eligibility. Of these, 30 did not meet the inclusion criteria, 27 declined to participate, while 114 were successfully recruited and randomised into either the RMZ-AF or AF-RMZ group (n=57 per group). A total of 114 patients were included in the analysis (Figure 1). Table 1 presents the patient demographic data. No statistically significant differences were observed between the groups.

Table 1 Baseline Characteristics of Patients

Figure 1 CONSORT diagram for the trial. CONSORT indicates Consolidated Standards for Reporting of Trials.

The time from remimazolam administration to LOC during anaesthesia induction was significantly shorter in the AF-RMZ group than in the RMZ-AF group (87.3 [25.7] s vs 132.3 [32.3] s, P<0.0001, Table 2). Similarly, the time from remimazolam administration to BIS ≤ 60 was significantly shorter in the AF-RMZ group than in the RMZ-AF group (168.2 [58.1] s vs 207.8 [61.6] s, P=0.0006, Table 2).

Table 2 Sedation Characteristics of Patients Receiving Remimazolam Combined with or Without Alfentanil for Anaesthesia Induction

No significant differences were found between groups in terms of anaesthesia duration, surgery duration, eyes-opening time, extubation time, or PACU stay (Table 2). The total administration of remimazolam did not differ significantly between groups (Table 3). However, remimazolam doses were more in the RMZ-AF group than in the AF-RMZ group at LOC (14.7 [12.3, 16.4] mg vs 9.9 [8.5, 11.0] mg, P<0.0001) and at BIS ≤ 60 (21.3 [17.5, 25.1] mg vs 18.4 [13.1, 22.6] mg, P=0.0058). No differences were found between the groups in terms of the total administration of alfentanil, ephedrine, rocuronium, or crystalloid infusion volume.

Table 3 Characteristics of Anaesthesia and Surgery in Patients Receiving Remimazolam Combined with or Without Alfentanil for Anaesthesia Induction

Table 4 presents the incidence of adverse events. Hypotension was the most common adverse event, but no difference was found between the RMZ-AF and AF-RMZ groups (28 [49.1%] vs 22 [38.6%], 95% CI: 1.3 [0.84–2.0], P=0.3454). The incidence of hypertension was 10.5% (n=6) in the RMZ-AF group and 15.8% (n=9) in the AF-RMZ group (95% CI: 1.5 [0.59–3.8], P=0.5808). Tachycardia occurred in 12.3% of patients in both groups. No patients in either group experienced bradycardia, injection pain, dysphoria, nausea/vomiting, awareness, delirium, or hiccups.

Table 4 Incidence of Adverse Event in Patients Receiving Remimazolam Combined with or Without Alfentanil for Anaesthesia Induction

No significant differences were observed in MBP, heart rate, SpO₂, or BIS values at any time point (Figure 2).

Figure 2 Changes in vital signs of patients receiving remimazolam combined with or without alfentanil for anaesthesia induction. Data are displayed as means (SD) (A–C) or medians (D). Data were compared using repeated-measures two-way analysis of variance (ANOVA) with Geisser-Greenhouse correction, followed by Bonferroni`s multiple comparisons test. (A) Drug: F (1, 112) = 0.8040, p=0.3718; Time: F (11, 1232) = 127.5, p<0.0001; Drug Ⅹ Time: F (11, 1232) = 1.597, p=0.0936; Subject: F (112.1232) = 8.416, p<0.0001. (B) Drug: F (1, 112) = 0.0362, p=0.8494; Time: F (11, 1232) = 11.92, p<0.0001; Drug Ⅹ Time: F (11, 1232) = 7.392, p<0.0001; Subject: F (112.1232) = 14.33, p<0.0001. (C) Drug: F (1, 112) = 1.045, p=0.3088; Time: F (11, 1232) = 11.43, p<0.0001; Drug Ⅹ Time: F (11, 1232) = 0.5367, p=0.8793; Subject: F (112.1232) = 4.385, p<0.0001. (D) Drug: F (1, 112) = 0.7292, p=0.3950; Time: F (8, 896) = 639.0, p<0.0001; Drug Ⅹ Time: F (8, 896) = 1.627, p=0.1131; Subject: F (112.896) = 3.800, p<0.0001. Abbreviations: RMZ, remimazolam; AF, alfentanil; MBP, mean arterial blood pressure; HR, heart rate; SpO2, pulse oximetry; LOC, loss of consciousness; BIS, bispectral index; PACU, post-anaesthesia care unit.

Discussion

This is the first reported randomised controlled trial investigating the interaction between remimazolam and alfentanil. The main finding of our results showed that the time to LOC and the doses of remimazolam required to reach LOC and BIS ≤ 60 during anaesthesia induction were shorter and lower, respectively, in the AF-RMZ group than in the RMZ-AF group. These results confirm our hypothesis that alfentanil enhances the sedative effects of remimazolam during anaesthesia induction in patients undergoing urological day surgery.

Drug interactions can be classified as synergism, additivity, or antagonism, regardless of whether one drug exerts an effect on its own.^14–17 During anaesthesia induction and maintenance, it is a common practice to use two or more drugs either successively or simultaneously. Combining sedatives and opioids has a synergistic effect, enhancing anaesthesia, reducing the dosage of both drugs, and minimising adverse events.¹⁸ For instance, the combination of propofol and alfentanil changed alfentanil’s pharmacokinetics by decreasing elimination clearance by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%.⁶ Although we did not conduct pharmacokinetic assessments in this study, we speculate that pretreatment with alfentanil can also affect the pharmacokinetics of remimazolam by decreasing elimination clearance and slowing distribution clearance, thereby enhancing the sedative effect of remimazolam.

Drug interactions may occur through the modulation of the action site.¹⁹ Therefore, understanding the mechanisms underlying these interactions is critical. The combination of propofol and alfentanil produced synergistic antinociceptive effects²⁰ through the inhibition of phosphorylated extracellular signal-regulated kinase 1/2, c-Fos protein²¹ and the adenylyl cyclase pathway.²² Propofol exerts sedative effects by potentiating GABA responses and activating GABA type A receptors (GABAARs).²³ Similarly, remimazolam exerts sedative effects by also acting on GABAARs.⁷ Alfentanil exerts its analgesic effect by acting on mu-opioid receptors (MOR). Since both GABAARs and MOR are co-expressed in some primary afferent neurons, it is plausible that propofol–alfentanil and remimazolam-alfentanil administration may activate the same neural pathways, thereby enhancing their sedative effects.

Alfentanil has been used as a sedative regimen in intensive care without causing prolonged respiratory depression.²⁴ Given that the time to LOC or BIS ≤ 60 and the doses of remimazolam required were significantly shorter or lower, respectively, in the AF-RMZ group compared with the RMZ-AF group, we concluded that alfentanil enhances the sedative effect of remimazolam. The peak effect of a bolus injection of alfentanil occurs at approximately 3–4 min,²⁵ while remimazolam reaches a peak effect at 2–3 min. By administering alfentanil immediately before remimazolam, the peak effect of both drugs overlaps, maximising remimazolam’s sedative efficacy. As the exact nature of their interaction – whether synergistic or additive – remains unclear, further investigation is required to elucidate the underlying mechanisms.

Combining alfentanil and midazolam is recommended in different clinical practices. The combination of remimazolam with alfentanil for anaesthesia during endoscopic retrograde cholangiopancreatography (ERCP), colonoscopy, and gastroscopy procedures showed fewer respiratory depression events and haemodynamic advantages than the propofol-alfentanil combination.^26–28 Hypertension, hypotension, and tachycardia were the major adverse events among the two groups; however, no differences were found between the groups in our trial. The awakening time was slightly longer, and the incidence of adverse events (nausea, abdominal pain, fatigue, dizziness, and abdominal distension) were lower in remimazolam-alfentanil group than that in the propofol-alfentanil group during gastroscopy.²⁷ The postoperative 15-item quality of recovery questionnaire score was higher, and the abdominal pain was lower in the remimazolam-alfentanil group than in the propofol-alfentanil group during ERCP procedure.²⁶ Thus, combining remimazolam and alfentanil may be a safe option for anaesthesia.

Sedative-hypnotic drugs and opioids are risk factors for post-operative nausea and vomiting (PONV), which can prolong recovery. None of the patients developed PONV during our trial. Consistent with a previous report, alfentanil reduced the incidence of PONV than fentanyl.²⁹ The use of rapidly metabolic sedative-hypnotic drugs and opioids for anaesthesia is effective in reducing the risk of PONV.³⁰

None of the patients developed emergence delirium (ED) during our trial. Intranasal alfentanil, in addition to oral midazolam, did not decrease sevoflurane-induced ED.³¹ Intravenous alfentanil decreased the incidence of ED in the PACU.³² Compared with intravenous injection, the bioavailability of intranasal alfentanil was reduced to 64.7%.³³ We infer that the different bio-availabilities of alfentanil result in this discrepancy in preventing ED.

Hiccups are a troublesome adverse event associated with remimazolam. Although remimazolam-induced hiccups are generally self-limiting, they are associated with the risk of regurgitation and aspiration, particularly in patients with a full stomach. No patients developed hiccups during this trial. The incidence of hiccups depends on the bolus rate of remimazolam administered during sedation induction.³⁴ We believe that remimazolam administration at a rate of 6 mg kg⁻¹ h⁻¹ during anaesthesia induction would be appropriate. No patients in our trial experienced injection pain, dysphoria, or increased awareness.

Although there was no significant difference in the incidence of adverse events between the two groups in this study, which differed from those of other studies,^26,27 the reasons may be differences in the study population, differences in drug dosage and administration methods, and the study sample size.

This study had several limitations. First, the trial focused exclusively on patients undergoing urological day surgery, limiting the generalisability of the findings to other populations. Further studies are needed to validate these conclusions in other contexts. Second, this was a single-blinded trial. Although the patients, surgeons, and data collectors were blinded to the group assignment throughout the process, the possibility of bias cannot be entirely excluded. Third, all patients were drawn from a single centre, and genetic and racial factors may limit the applicability of our findings to other populations. Further multi-centre clinical trials are required to confirm this conclusion.

Conclusion

In conclusion, alfentanil enhances the sedative effects of remimazolam during anaesthesia induction in patients undergoing urological day surgery. The combination of remimazolam and alfentanil for general anaesthesia would improve efficacy, reducing the adverse effects and dosage of drug. But the potential mechanisms need further study.

Abbreviations

MBP, mean arterial blood pressure; CI, confidence interval; GABA_A, gamma-aminobutyric acid receptor subunit A; ASA, American Society of Anaesthesiologist; PACU, post-anaesthesia care unit; SpO₂, pulse oximetry; BIS, bispectral index; LOC, loss of consciousness; IQR, interquartile range; ASD, absolute standardized difference; ANOVA, analysis of variance; RMZ, remimazolam; AF, alfentanil.

Data Sharing Statement

The data generated during the current study are available from the corresponding author on reasonable request.

Ethic Approval

This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (identifier: 2022-KY-E-302; Chairperson: Prof. Songqing He) on 13 September 2022 and was registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn; registration number: ChiCTR2200064130, principal investigator: Xuehai Guan; date of registration: 27 September 2022). Written informed consent was obtained from all patients before enrolment. This trial was performed at the First Affiliated Hospital of Guangxi Medical University in accordance with the Declaration of Helsinki and CONSORT guidelines.

Acknowledgments

This study was supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2022GXNSFAA035628, 2024GXNSFAA010222), the Clinical Research “Climbing” Program of the First Affiliated Hospital of Guangxi Medical University (YYZS2022005), the Guangxi Zhuang Autonomous Region Health Commission’s Self-Fund Research Project on Western Medicine (Z-A20230492), and the Guangxi Zhuang Autonomous Region Traditional Chinese Medicine Appropriate Technology Development and Promotion Project (GZSY22-59). The funder had no role in the concept, patient recruitment, data collection, analysis, interpretation, trial design, or making the decision to submit for publication.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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Introduction

Coronary Heart Disease (CHD), as one of the leading causes of death and disability worldwide, has become a significant public health concern.¹ Advances in medical technology have significantly improved the survival rates of CHD patients, enabling an increasing number of individuals to live with the condition for extended periods and resume normal activities. However, quality of life issues during the rehabilitation process, especially sexual health issues, are increasingly attracting widespread attention. Research indicates that sexual dysfunction is prevalent among CHD patients² and can be attributed to multiple factors, including the disease itself, side effects of treatment, and psychological stress.³ There is a close internal link between heart health and sexual health, CHD may directly lead to sexual dysfunction by affecting blood vessel function and blood circulation, and sexual activity itself as a physical activity, will produce a certain load on heart function, thereby causing patients to worry about sexual safety.⁴ Therefore, comprehensive research on heart health and sexual health as a whole will not only help reveal the interaction mechanism between the two, but also provide patients with more comprehensive rehabilitation guidance.

Sexual health, as defined by the World Health Organization (WHO) is an integral component of overall well-being, encompassing physical, psychological, and social dimensions.⁵ For patients with CHD, the disease and its treatments, including surgery and medication, often negatively impact sexual activity, leading to issues such as erectile dysfunction, reduced libido, and decreased sexual satisfaction.⁶ In addition, psychological problems such as anxiety and depression after the illness further aggravate the problem of sexual health.^7,8 Sexual health issues not only affect the individual quality of life of patients, but can also have a negative impact on marital relationships and family harmony.⁹ However, due to cultural, social and doctor-patient relationship, sexual health issues are often ignored or avoided in clinical practice. Patients do not come forward because of shame or lack of trust in the doctor, and the doctor may fail to initiate such discussions because of limited time, lack of expertise, or fear of offending the patient.

The topic of sex is particularly sensitive within Chinese culture. Influenced by traditional beliefs, sexual issues are often considered taboo in many cases and rarely discussed openly even in medical settings.⁸ This cultural background makes CHD patients face more complex sexual health issues during recovery. Although some studies have pointed out that sexual counseling has an important role in helping patients resume sexual life,¹⁰ systematic and standardized sexual counseling services have not yet been formed in China. There is a significant gap between patients’ needs and the services they actually receive, affecting their full recovery. This gap not only hinders the full recovery of patients, but also highlights the urgency of in-depth exploratory counseling and its influencing factors.

The lack of patient perspective is also a shortcoming in the current study. The existing literature mainly focuses on the perspective of medical staff or the impact of disease, and pays less attention to patients’ own experiences and needs.^8,11,12 This lack is due to a number of reasons. First, cultural taboos prevent patients from speaking openly about sexual health problems, making it difficult for researchers to obtain first-hand information from patients.⁸ Second, in clinical practice, medical professionals often prioritize the acute symptoms of heart disease over the sexual health needs of patients, thus limiting the systematic exploration of patient perspectives.^13,14

Based on the Comprehensive Framework for Implementation Research (CFIR) and the Capability, Opportunity, Motivation-behavior model (COM-B), this study explores the facilitators and barriers to the implementation of sexual counseling through qualitative research methods. Heart health and sexual health, two key areas that affect patients’ quality of life, face the challenge of stigmatizing discussions in many cultures, especially in the context of China, where such traditional beliefs are deeply ingrained. Combining these two theories, this study provides a comprehensive understanding the implementation status of sexual counseling in CHD patients from the perspective of both the supply and demand of sexual counseling through in-depth interviews, provides theoretical support for the formulation of more effective intervention strategies, and provides specific recommendations for policy makers, healthcare administrators and front-line medical professionals in practice.

Methods

Study Design and Participants

This study uses a describe qualitative research to assess the determinants influencing the implementation of sexual counselling. Purposive sampling method was used to select medical staff and patients from the cardiovascular department of the First Affiliated Hospital of Xinxiang Medical College, Henan Province in China from November 2023 to January 2024 as the study objects. Doctors and nurses who experience in treating or caring for patients in the cardiovascular department for more than 2 years are selected. Patients diagnosed with coronary heart disease, aged 18 years or older, had a stable sexual partner, maintained a normal sexual life before the disease, and had no communication disorders were selected. Patients with CHD combined with heart failure and mental illness were excluded.

Theoretical Framework

CFIR and COM-B model were used as theoretical guidance to guide data collection and analysis. CFIR is divided into five dimensions and 39 components, including intervention characteristics, inner setting, outer setting, participant characteristics and implementation process.¹⁵ The framework serves as a determinant framework that offering researchers a structured approach to analyzing and understanding the various factors that influence the successful implementation of a project, policy, or intervention.¹⁶ Based on CFIR, this study analyzed factors such as intervention characteristics, environment and participant characteristics in the implementation of sexual counseling from the perspective of medical staff. For example, “How do you think to conduct sexual counseling for patients with CHD (eg, way, method, content)?” explores intervention characteristics, “What do you think are the factors that sexual counseling does not conducted in patients with CHD?” examines the potential influence of external environment (eg, culture) and internal environment (eg, resources), and “Do you know anything about sexual counseling for cardiovascular patients?” assesses individual characteristics.

The COM-B model comprising capability, opportunity and motivation-behavior,¹⁷ This model examines the behavioral changes of people from three dimensions of ability, opportunity and motivation,¹⁸ which is used to guide the understanding of relevant behaviors, establish the behavioral goals, and lay the foundation for designing intervention measures.¹⁸ Based on the COM-B model, this study analyzed the determinants of sexual counseling seeking behavior from the perspective of patients. Such as “Do you know anything about having sexual life safely after illness?” assesses psychological ability, “Who do you want to get it from, and in what way (eg, telephone, brochure)?” explores physical opportunities, and “What do you think are the reasons for not seeking counseling?” reflects reflective motivation.

Research Team

Our team consisted of four researchers, a female professor responsible for the design and quality control of the study, two Ph.D. researchers (two females) involved in the collection and analysis of the data, and another female professor with extensive experience in qualitative research who was responsible for negotiating and determining the code.

Data Collection

Two researchers established good relationships with participants. Face-to-face semi-structured interviews were used in this study. An interview outline was developed for medical staff and patients based on CFIR and COM-B models. After the interview outline is drawn up, researchers familiar with the subject are invited to revise it. After the pre-experiment, the interview outline was modified again to form the final interview outline (Appendix 1). Each interview lasted 30 to 50 minutes. Before the interview, the demographic data of the participants were collected, the purpose of the interview was informed, and the interview was started with the consent of the participants. During the interview, two researchers participated in the interview and collected data simultaneously through notes and recordings. The interview was conducted in a quiet and undisturbed environment. After the interviews, the two researchers transcribed the interviews verbatim into text within 24 hours. A researcher used the notes taken during the interview to supplement and verify the interview text. Subsequently, the two researchers summarized the data and analyzed whether new topics appeared to determine the saturation of information. When the information reached saturation, the number of participants in the interview was the sample size of this study.

Data Analysis

After the interviews, NVivo11 software was used to encode the data. Data analysis followed the thematic analysis method proposed by Braun and Clarke.¹⁹ The analysis process included steps such as becoming familiar with the interview data, generating initial codes, summarizing themes, reviewing themes, and naming themes. First, two researchers read each transcript word for word and took preliminary notes to familiarize themselves with the data. Next, by reading the data line by line, the researcher marked the words and sentences related to the research questions and openly coded the data. Subsequently, similar or related codes were sorted together to form a preliminary coding framework. After the initial codes are generated, the researchers summarized and organized these codes, identified potential topics, and brought together all the codes and data fragments related to each potential theme to form a preliminary framework of themes. Finally, each theme was checked for consistency with the relevant codes and the entire data set, and individual themes were mapped into the CFIR and COM-B models.

Researcher Reflexivity

In this study, two researchers systematically reflected on the potential influence of their personal backgrounds, perspectives, and experiences on the research process through detailed reflective journals and regular team discussions. To enhance the reliability of the results, the study used data source triangulation (collecting data from both medical staff and patients’ perspectives) and researcher triangulation (two researchers independently coded, which was reviewed and agreed upon by a third researcher). In addition, methodological rigor and robustness of study findings were ensured by checking preliminary results with participants, confirming data saturation (new information no longer appears), and following the COREQ 32-item checklist.

Ethics

This study was approved by the Ethics Committee of the First Affiliated Hospital of Xinxiang Medical College (No. (Nọ): EC-022-005). The researchers adhered to the Declaration of Helsinki. The information collected in the study was strictly confidential and anonymous. Letters were used to replace the patients’ name in the study, “D” stands for doctor, “N” stands for nurse, “M” stands for male patient, and “F” stands for female patient. Participants were informed that they could withdraw from the study at any time and/or refuse to answer any questions.

Results

A total of 23 participants were included in this study, including 10 medical staff and 13 patients with CHD. The medical staff included 8 doctors and 2 nurses, 7 of whom were male and 3 were female (Table 1). Among the patients, there were 10 males and 3 females, aged mainly between 41 and 50 years old, accounting for 46.2%, most of the patients had a junior high school education (Table 2).

Table 1 Demographic Data with Medical Staff (n=10)

Table 2 Demographic Data with Patients (n=13)

Interview Results of Medical Staff

The themes and subthemes derived from the study are shown in Table 3.

Table 3 Facilitators and Barriers Themes with Medical Staff

Intervention Characteristics

Integrate into Daily Health Education

Medical staff recommend integrating sexual counseling into routine health education to reduce the embarrassment of patients and medical staff when discussing sexual health issues. By naturally embedding the content of sexual health education into routine health education, sexual counseling can become a part of routine care, thereby alleviating the psychological burden on patients when asking questions. This approach sends a clear message to patients that sexual health is part of a comprehensive health management process and that they can feel free to ask questions without feeling uncomfortable or shy.

D9: Incorporate knowledge about sexual life into daily health education so that it is not easy to cause discomfort to patients. There is no need to talk about it specifically. Just give patients a signal so that those who have questions can actively ask medical staff.

Use of Information Brochures

Medical staff recommend using detailed health education brochures that patients can read in private. This approach effectively protects patients’ privacy and enables them to obtain sexual health information in an undisturbed environment. At the same time, the brochures can provide guidance on how to obtain further sexual counseling, reminding patients to actively seek help when needed. This approach not only makes it easier for patients to access information, it also increases the likelihood that they will proactively contact their medical staff, thereby improving the overall effectiveness of care.

D8: You can provide patients with a health knowledge booklet and write the content in the booklet as detailed as possible. This can not only protect the patient’s privacy, but also send a signal to the patient, allowing the patient to ask medical staff if he has any questions.

Personalized Consultation Based on Patient Needs

Medical staff emphasize that sexual counseling must be tailored to the individual needs of patients to ensure that their specific circumstances and special requirements are met. Each patient’s background, medical condition, and focus on sexual health issues may be different, so sexual counseling cannot be a one-size-fits-all approach. Medical staff should fully understand the patient’s personal experience, cultural background and psychological state so as to provide targeted advice and support. Personalized sexual counseling can not only more accurately address patients’ specific problems, but also improve patient satisfaction and treatment outcomes.

N7: When doing sexual counseling, you need to first understand the patient’s condition and educate the patient based on his or her needs.

Misconceptions About Specialists

Patients often mistakenly believe that cardiologists focus only on the treatment of heart disease. This misunderstanding stems from a narrow understanding of the role of the cardiovascular physician, which leads patients to view sexual health issues as a separate area unrelated to heart disease. As a result, they are unaware that cardiologists can provide valuable assistance, leading to a lack of trust in the physician’s overall abilities and limiting the willingness to proactively seek help.

D4: Some patients believe that specialists are responsible for their own treatments and are unaware that doctors have knowledge in this area. They mistakenly believe that cardiologists only treat heart problems.

Outer Setting

Benefit from External Learning

Healthcare professionals who have received sexual counseling training or have participated in sexual counseling practices have found these experiences to be very beneficial to their professional development and patient care. The training made them realize the importance of sexual health knowledge in practical work and improved their ability to identify and solve patients’ sexual health problems. Through systematic training, healthcare professionals can not only provide effective sexual counseling to help patients understand and manage disease-related sexual issues, but also significantly improve the overall quality of life of patients.

D10: I have learned relevant guidance when I was training in other hospitals. It clearly stated how long it takes to resume sexual intercourse after myocardial infarction or PCI surgery. The hospital also provided patients with rehabilitation and guidance in this aspect, which improved their quality of life.

Traditional Culture’s Barriers to Sexual Counseling

Medical staff believe that traditional culture has a significant impact on patients’ ability and willingness to discuss sexual health issues. In Chinese culture, sex is considered a private and taboo topic, which means that even if patients have concerns, they may choose to keep silent due to embarrassment and shame. Especially when communicating with medical staff of the opposite sex, patients’ resistance is more obvious. Traditional gender roles and privacy concepts further aggravate their shyness and anxiety.

D6: In China, sex is a very sensitive topic, and even if patients have sexual problems, they will avoid talking about it in most cases.

D10: Influenced by traditional culture, I am relatively conservative and embarrassed to ask. I also won’t take the initiative to tell patients these things because I don’t know whether they need it or not.

N7: When facing patients of the opposite sex, sometimes patients are reluctant to speak because they feel embarrassed. For example, male patients are embarrassed to speak to female doctors.

Inner Setting

Lack of Suitable Environment for Consultation

Lack of a privacy is one of the most important barriers to sexual counseling. The noise, high turnover and small space in the wards limit the possibility of private and sensitive discussions. In this environment, it is difficult for patients to open up about their sexual health concerns and needs. In addition, the presence of other patients and medical staff may make patients feel embarrassed and reluctant to ask sexual questions, causing them to feel ignored and affecting their acceptance of sexual counseling.

D10: Chinese culture are relatively conservative when discussing sexual topics, and sexual counseling must be conducted in a secret environment.

N3: The environment in the ward is quite noisy. It is not appropriate to conduct sexual counseling in the ward. It is better to have a private environment.

Characteristics of Individuals

Willingness to Learn and Implement Evidence-Based Practice

Many medical staff said that they would be willing to learn sexual counseling knowledge and apply it in clinical practice if evidence-based evidence and relevant training were available. Systematic training allows them to acquire best practices and the latest research, thereby enhancing the professionalism and effectiveness of their consultation. In summary, medical staff hope to improve their sexual health knowledge through scientific training in order to better meet the needs of patients.

D1: As long as I have evidence-based guidance on what to do, I am willing to give guidance to patients, and I am willing to learn and work on sexual counseling.

N7: Patients have this need and sexual life is very important to them, but they are unwilling to speak up. I think medical staff should actively carry out this work, and I am willing to join in this work.

Resistance to Sexual Counseling

Some medical staff are reluctant to provide sexual counseling, mainly due to lack of knowledge and interest in sexual health issues. On the one hand, many medical staff feel uncomfortable when providing sexual counseling due to lack of professional training and lack of knowledge. On the other hand, high workloads and tight schedules limit their ability to pay attention to and deal with patients’ sexual health issues.

D2: I have never thought about studying relevant literature. Compared with the disease itself, this is not important. Even if I know the relevant knowledge, I am still unwilling to carry out health education or consultation on sexual life.

D5: Doctors have limited energy and there are too many patients, they don’t have time to deal with these.

Patient Interview Results

The themes and subthemes derived from the study are shown in Table 4.

Table 4 Facilitators and Barriers Themes with Patients

Physical Capability

Physical Condition

Physical condition is an important barrier to sexual counseling for patients. Some patients tend to feel uneasy about changes in their physical condition, and even if they do not feel any discomfort in their daily activities, their anxiety and worry make them hesitant and unwilling to take the initiative to consult medical staff. Concerns about their physical condition limit their access to sexual health issues.

M1: I didn’t feel any discomfort and had no symptoms after light physical labor. Considering the illness, I started having sex after a while, and I didn’t have the awareness to ask for advice on when to start having sex.

Physiological Condition

Some patients believe that their sexual function declines with age, and even if they have sexual problems after becoming ill, they do not think it is necessary to seek professional consultation.

M9: After illness, I felt that the quality of my sexual life was not as good as before illness. However, as I got older, I had fewer sexual intercourses, so I was not willing to seek sexual counseling.

Psychological Capability

Misconception

Some patients have the wrong perception that sex is a completely personal issue, so they are ashamed to ask or discuss it with others. They do not seek sexual counseling not only because they are ashamed but also because they lack relevant knowledge and do not know where to get sexual counseling. In addition, due to the influence of sociocultural factors, they often have doubts about seeking professional support, which also exacerbates patients’ neglect of sexual health issues.

M13: I didn’t know that coronary heart disease affects sexual function, and I didn’t know that I could get sexual counseling from medical staff. Medical staff didn’t mention these things to me. Besides, sexual life is a personal matter, and I’m embarrassed to ask others.

Lack of Knowledge

Patients lack knowledge about sex. They often only realize the impact of disease on physical health, but do not realize that disease can also affect the quality of sexual life. Furthermore, because medical staff fail to offer patients with detailed information about sexual health during discharge instructions, patients were unable to obtain adequate sexual health knowledge.

F7: I did not know that coronary heart disease would affect sexual function. I just thought that after the operation, I was afraid to have sex. There was no medical staff to provide relevant education and guidance, and I did not know that I could seek sexual counseling from medical staff.

M5: I have not paid attention to whether coronary heart disease has any impact on my sexual life. When I was discharged from the hospital, the doctor informed me of the precautions I should take at home about the disease, but did not provide me with any knowledge about sexual life. Therefore, I had no awareness of seeking medical advice when I had sexual health problems.

Opportunity

Physical Opportunity

Social Environment

Social environment inhibits patients from discussing sexual health issues. People around them avoid talking about sexual health issues, and this atmosphere of silence makes them feel embarrassed to speak up and unable to take the initiative to talk about related topics or seek help.

M11: None of my friends talk about sex, and I am embarrassed to talk about it.

M10: I don’t know this knowledge either, and the people around me also lack this knowledge, so I can’t consult others.

Social Opportunity

Social Culture

Cultural norms and the perception that sexual topics are highly private prevent patients from discussing these sensitive topics with their healthcare providers. In Chinese culture, talking about sex is considered taboo, and even if patients realize they need help, they often remain silent due to cultural pressure.

M6: I am relatively conservative and think that sex is a private topic. I have never dared to ask other people. I have looked up relevant questions on the Internet and in books. I am embarrassed to consult medical staff.

M3: I think sexual topics are personal privacy and I am unwilling to mention them to outsiders. I have never asked anyone else and I don’t know that medical staff can provide relevant knowledge.

Motivation

Reflective Motivation

Self-Assessment

Patients often rely on self-assessment for sexual health issues, believe that they do not need sexual counseling if they do not have obvious symptoms, and lack the initiative to discuss sexual health issues with medical staff. This misconception causes them to ignore potential sexual health problems and weakens their willingness to seek professional guidance.

M1: I thought there was nothing wrong with my body, so I didn’t consult any medical staff and I didn’t know whether the disease had any impact on my sexual function.

Psychology

The patient’s psychological state has a negative impact on his or her physical health and the quality of his or her sexual life. When patients feel anxious or fearful about their illness or treatment outcomes, this emotional state can exacerbate their concerns about their sexual life, which can affect their sexual function and overall life satisfaction.

F8: After the operation, I have no symptoms after daily activities, but I am afraid of an acute attack of the disease and dare not have sex. I wonder if I can consult the medical staff of the cardiovascular department.

Automatic Motivation

Necessity of Things

Despite multiple barriers, some patients are eager to learn about the impact of the disease on their sexual health and believe that acquiring sexual health knowledge is crucial to improving their quality of life. These patients hope to obtain detailed sexual health knowledge and hope to get help from medical staff.

M6: Patients lack the knowledge about safe sex after the disease and are afraid to have sex. They hope to learn about this from medical staff and feel it is necessary to learn about it.

F4: Some patients are eager to learn relevant knowledge, hope that medical staff can provide relevant knowledge, and are willing to make changes.

Discussion

Based on the CFIR and COM-B models, this study systematically analyzed the determinants of sexual counseling for patients with CHD and found that there are many factors that affect sexual counseling, involving multiple levels such as medical staff, patients and their social environment. Most of the research results are consistent with previous studies.^11,12,20 Research shows that many medical staff believe that sexual counseling is difficult to implement directly. They suggest embedding sex-related knowledge into health education. This implicit intervention strategy can reduce patients’ embarrassment and discomfort, and patients may be more likely to accept it. This is consistent with a study, this study shows that due to the confidentiality of sexual topics, it is difficult for medical staff to provide sexual counseling. The study found that patients prefer to obtain sexual knowledge through indirect channels such as health education, WeChat and so on.⁷ However, this approach may also result in some patients being unaware of the availability of sexual counseling, thereby missing out on the opportunity to obtain targeted intervention. Therefore, future interventions should find a balance between implicit and explicit approaches to protect patient privacy while ensuring the effectiveness of information delivery.

The study found that some medical staff are resistant to sexual counseling, partly because they lack relevant knowledge and guidance. Many medical training programs do not pay enough attention to sexual health, and medical staff lack knowledge about the sexual health of patients with coronary heart disease.^13,14 This makes medical staff lack the confidence and ability to discuss such issues. Even if they recognize the importance of sexual health, they are often afraid to talk about it. On the other hand, high workload is an important factor that causes medical staff to ignore sexual health issues. Clinical medical staff face a large number of daily tasks and emergencies. Due to limitations of time and resources, they can only deal with patients’ disease treatment and lack the energy to pay attention to sexual health issues. In this case, patients’ sexual health issues become a secondary issue.¹³ Although sexual health is critical to a patient’s quality of life, it is often neglected due to time and resource constraints on medical staff.

Culture is an important factor affecting the implementation of counseling. In traditional Chinese culture, the moral constraints of Confucianism,²¹ the implicit expressions of Taoism, and the restraint concept of Buddhism²² have led Chinese to believe that sexual issues are private issues, or even taboo topics. This leads to patients often choosing to look up information on their own or not deal with it when they have sexual health problems.^23,24 This study also reached a similar conclusion. The perception and attitudes towards sexuality among Chinese people not only influence how patients approach sexual health issues but also affect how healthcare professionals address these concerns. Many medical staff are worried that discussing sexual issues will cause discomfort or embarrassment to patients, which leads them to avoid discussing them in actual work. This is consistent with the research views of Emily K. Hyde et al.¹¹ Cultural barriers lead to the neglect of sexual health issues in clinical practice. Compared with Western countries, patients in China are more reluctant to take the initiative to raise sexual health issues,¹⁴ resulting in medical staff not knowing how to intervene, which makes greater challenges to the promotion of sexual counseling in China. Therefore, future interventions need to gradually guide patients and health care professionals to discuss sexual issues more openly while respecting cultural backgrounds.

Despite the many obstacles, this study also found some factors that are conducive to the implementation of sexual counseling. For example, some medical staff said that they are willing to conduct sexual counseling if there is evidence-based guidance. This shows that by providing scientific evidence and practical operation guidelines, the enthusiasm of medical staff can be stimulated and the promotion of sexual counseling can be promoted. In addition, some patients expressed their desire to acquire sex-related knowledge and were willing to accept guidance from medical staff, which provided a good basis for the implementation of sexual counseling.

This study provides insights into the implementation of sexual counseling in the Chinese context and has certain implications for future research. By integrating CFIR and COM-B models to combine determinants from both supply and demand sides, this study transcends a single healthcare professional perspective, revealing the interplay between cultural taboos and environmental constraints and its implications for systemic interventions, offering valuable insights for countries with conservative cultural backgrounds. This study emphasizes the importance of patient education and suggests that implicit education (eg, manuals) is more suitable for sensitive environments. It also preliminarily identifies barriers and opportunities and suggests measures such as training, improving the consultation environment (eg, private space), and incorporating sexual health into cardiac rehabilitation guidelines to alleviate limitations in implementation. Meanwhile, future extension of these findings to multi-regional and multi-cultural studies is encouraged to verify their applicability.

Limitations

The study also has some limitations. First, the generalizability of the results may be affected by the limited sample size. Future studies should increase the sample size, especially by increasing the participation of patients and medical staff from different regions and cultural backgrounds. Secondly, the depth of qualitative research depends on participants’ willingness to express and the richness of interview data. Although this study ensures the adequacy of the subject through data saturation, some participants may not fully disclose their experience due to cultural taboos or personal reservations, which may limit the exploration of some potential problems. In addition, while the research team reduced subjective bias through reflection and triangulation, the researcher’s interpretation of the data may still be influenced by personal perspective. Therefore, future studies may consider combining quantitative studies to further verify the comprehensiveness of the results.

Conclusion

This study systematically analyzed the multiple factors that affect the implementation of sexual counseling for patients with CHD in China. The results showed that the implementation of sexual counseling was constrained by the knowledge and attitudes of medical staff, the counseling environment, the physical abilities and psychological barriers of patients, and the sociocultural background. Nevertheless, some medical staff and patients have a positive attitude towards sexual counseling, which provides a basis for promoting the implementation of sexual counseling. In the future, On the basis of respecting cultural background, we should explore in depth the effective intervention measures for the implementation of promotional counseling to comprehensively improve the quality of life of patients.

Data Sharing Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Ethics Approval and Informed Consent

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The First Affiliated Hospital of Xinxiang Medical University (No: EC-022-005).

Consent for Publication

All participants signed informed consent, including permission to publish anonymous responses and direct quotes.

Acknowledgments

We thank all the researchers and participants who participated in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Disclosure

The authors have no relevant financial or non-financial interests to disclose for this work.

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2. Brandis Kepler S, Hasin T, Benyamini Y, Goldbourt U, Gerber Y. Frequency of sexual activity and long-term survival after acute myocardial infarction. Am J Med. 2020;133(1):100–107. doi:10.1016/j.amjmed.2019.06.019

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6. Steinke EE, Mosack V, Hill TJ. The influence of comorbidities, risk factors, and medications on sexual activity in individuals aged 40 to 59 years with and without cardiac conditions: US National Health and Nutrition Examination Survey, 2011 to 2012. J Cardiovasc Nurs. 2018;33(2):118–125. doi:10.1097/JCN.0000000000000433

7. Wu X. Investigation and Countermeasures of Sexual Quality of Life After PCI [Master]. Guangxi Medical University; 2019.

8. Zhang F, Li Y, Shi Z, Wang A. Sexual experience in patients with coronary heart disease: a descriptive phenomenological study. Sci Rep. 2024;14(1):9968. doi:10.1038/s41598-024-60496-7

9. Günzler C, Kriston L, Harms A, Berner MM. Association of sexual functioning and quality of partnership in patients in cardiovascular rehabilitation–a gender perspective. J Sex Med. 2009;6(1):164–174. doi:10.1111/j.1743-6109.2008.01039.x

10. Xu F, Ming Q, Hou L. The effect of sex counselling in the sexual activity of acute myocardial infarction patients after primary percutaneous coronary intervention. Acta Cardiol. 2015;70(4):460–464. doi:10.1080/ac.70.4.3096894

11. Hyde EK, Martin DE, Rieger KL. Factors shaping the provision of sexual health education for adults with acute coronary syndrome: a scoping review. Patient Educ Couns. 2020;103(5):877–887. doi:10.1016/j.pec.2019.11.017

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14. Wang P, Ai J, Davidson PM, Slater T, Du R, Chen C. Nurses’ attitudes, beliefs and practices on sexuality for cardiovascular care: a cross-sectional study. J Clin Nurs. 2019;28(5–6):980–986. doi:10.1111/jocn.14692

15. Zhang Q, Pang D, Hu J, Wang Z. An interpretation of the constituent elements of the Comprehensive Framework for Implementation Research (CFIR). Chin J Evid Based Med. 2021;21(3):355–360.

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A landmark 30-year study of over four million women in England has revealed that women with endometriosis-associated infertility are significantly more likely to become pregnant compared to those with infertility from other causes.

Presented today at the 41st Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), the findings offer renewed optimism for millions of women living with endometriosis who are hoping to conceive. 

Endometriosis is a long-term condition in which tissue similar to the lining of the womb grows outside the womb, often causing severe pelvic pain and infertility. Globally, it is estimated to affect 190 million women and is recognised as a leading cause of infertility.

This study was conducted as part of the EU FEMaLe (Finding Endometriosis through Machine Learning) consortium. Led by Dr. Lucky Saraswat from the Aberdeen Centre of Women’s Health Research, University of Aberdeen, together with researchers from the Centre for Reproductive Health at the University of Edinburgh, the research team carried out the largest and longest population-based study of its kind, analysing linked primary care, secondary care and maternity records for more than four million women in England who presented with infertility or symptoms related to endometriosis between 1991 and 2020.

Of the 4,041,770 women aged 13-50 years who attended primary care with infertility (n=245,994) or other symptoms of endometriosis, 111,197 had a surgically confirmed diagnosis of endometriosis via laparoscopy or laparotomy over the 30-year period. The overall population prevalence of female infertility across the population during the study period was 48.9 per 1,000 women, with highest rates observed among women aged 30 to 39.

Among those with infertility, 6.1% (14,904) had surgically confirmed endometriosis. Of these, 57.4% (8,556) experienced infertility before their diagnosis, underlining the ongoing delays in recognition and diagnosis of endometriosis.

The study reaffirmed a strong association between the condition and fertility challenges, showing that women with infertility were more than twice as likely to be diagnosed with endometriosis compared to women without infertility.

However, when examining pregnancy outcomes, women with endometriosis-associated infertility had a four times higher chance of conception compared to women with infertility from other causes, including ovulatory dysfunction, tubal factors, and unexplained infertility. In total, 40.5% of women with an endometriosis diagnosis (regardless of their infertility status) had at least one pregnancy during the study period. 

Reflecting on the potential explanations for this result, Dr. Saraswat said, “Endometriosis can vary in how it affects fertility. Women with milder forms may retain good reproductive potential, especially if the condition is diagnosed and managed early. There’s also moderate-quality evidence suggesting that laparoscopic surgery can improve pregnancy rates in some with endometriosis.”

She added that women with the condition may also be more likely to seek help earlier because of heightened awareness about the link between endometriosis and infertility. 

“While fertility remains multifactorial, with factors such as age playing a significant role, our findings offer robust, evidence-based data that can significantly enhance fertility counselling for women newly diagnosed with endometriosis – including information on the likelihood of infertility, overall pregnancy rates and outcomes, and how those outcomes compare to other causes of infertility.”

“These insights can empower women to make informed reproductive decisions“, she said. “They also provide a strong foundation for future research into how factors such as disease stage, site, surgical treatment and use of assisted reproduction influence pregnancy outcomes in women with endometriosis.” 

This study shows that women with endometriosis-related infertility are significantly more likely to conceive than those with other infertility causes. These findings provide valuable reassurance for patients and underscore the importance of early diagnosis and tailored treatment strategies.”

Professor Dr. Anis Feki, Chair-Elect of ESHRE

The study abstract will be published today in Human Reproduction, one of the world’s leading reproductive medicine journals.

Maintaining a healthy lifestyle-specifically, a diet rich in fibre but light on red/processed meat, regular exercise, not smoking, and sticking to a normal weight-is linked to a significantly lower risk of diverticulitis, finds a large long term study, published online in the journal Gut.

What’s more, these 5 components seem to offset the effects of inherited genes, the findings indicate.

Diverticulitis occurs when ‘pouches’ develop along the gut and become inflamed or infected in the wall of the large intestine (colon), explain the researchers. It’s a common cause of hospital admissions and a major reason for emergency colon surgery, they add.

Genetic and environmental factors, including lifestyle, contribute to the development of the condition, but it’s not clear exactly how these factors interact or the extent to which lifestyle might offset the genetic risk, they say.

To shed more light on this, the researchers derived an overall healthy lifestyle score (0-5) for diverticulitis from survey responses for 179,564 participants drawn from three prospective studies: the Nurses’ Health Study (NHS), NHSII, and the Health Professionals Follow-Up Study.

The score was based on 5 elements that have independently been associated with heightened risks of developing diverticulitis: smoking; weight (BMI); physical activity; fibre intake; and red/processed meat intake. 

The association between this score and incident diverticulitis was confirmed among 30,750 participants in the Southern Community Cohort Study (SCCS). 

Genetic risk was assessed using a polygenic risk score (PRS) in 36,077 people with available genotype information. 

During a monitoring period of 20 years, 10,299 new cases of diverticulitis were recorded. The 5 lifestyle factors were each significantly associated with the development of the condition. 

For example, compared with participants with a BMI below 25, those who were overweight were 32% more likely to develop diverticulitis, while those who were obese were 44% more likely to do so. 

Participants who had formerly or who were still smoking were, respectively, 17% and 13% more likely to be diagnosed with diverticulitis than those who had never smoked. And higher levels of physical activity were associated with a 16% reduced risk compared with lower levels. 

While higher fibre intake was associated with a 14% lower risk, higher red meat intake was associated with a 9% increased risk. 

And every 1-point increase in healthy lifestyle score was associated with a 12% lower risk of diverticulitis. Participants with a score of 5 were 50% less likely to be diagnosed with the condition than those with a score of 0.

The findings were consistently observed across all three studies and in different racial groups.

The association between healthy lifestyle score and incident diverticulitis was confirmed among 30,750 participants in the Southern Community Cohort Study (SCCS). 

Some 2183 new cases of diverticulitis were reported during an average monitoring period of nearly 12 years in this group. Those with a healthy lifestyle score of 3–5 had a substantially lower risk (31%) than those with a score of 0. 

Genetic risk was assessed using a polygenic (cumulative) risk score (PRS) in 36,077 people with available genotype information in the NHS, NHSII, and HPFS groups.

There were no notable differences in lifestyle factors across PRS categories, but PRS was significantly associated with incident diverticulitis. For each unit increase in PRS, the risk increased by 58%, and was particularly evident among those under the age of 60. 

And a healthy lifestyle seemed to offset genetic susceptibility to the condition. For example, those in the lowest PRS category and with a healthy lifestyle score of 4-5 were 37% less likely to develop diverticulitis compared to those with a score of 0.

Similarly, those with a medium PRS were 48% less likely to do so, while those in the highest PRS category were 50% less likely to do so. Further analysis showed that adopting a healthy lifestyle might prevent 23–42% of diverticulitis cases across PRS categories.

And when the effect of PRS and a healthy lifestyle score were combined, those in the highest PRS category with a healthy lifestyle score of 0 or 1 were 5 times more likely to develop diverticulitis than those in the lowest PRS category with a score of 4 or 5. 

The findings were further validated in the Mass General Brigham Biobank (MGBB).

This is an observational study, and as such, can’t establish cause. And the researchers acknowledge that ascertainment of diverticulitis was based on different approaches across the different studies.

Nevertheless, they conclude: “Our data provide consistent evidence from multiple data sets indicating that adherence to a healthy lifestyle is linked to a reduced risk of developing diverticulitis, irrespective of one’s genetic predisposition.”

A real-world, multicenter study of 67 evaluable patients treated with fecal microbiota, live-jslm (RBL), demonstrated a 77.6% treatment success rate at 8 weeks for preventing recurrent Clostridioides difficile infection (rCDI), with 87% maintaining remission at six months. These findings support RBL’s safety and efficacy beyond controlled clinical trials in an elderly, comorbid population frequently exposed to multiple rCDI risk factors.¹

What You Need To Know

RBL achieved a 77.6% treatment success rate at 8 weeks and 87% sustained remission at 6 months in a high-risk, elderly population.

The treatment was well tolerated, with minor adverse events reported in only 5 patients.

Advanced age and multiple CDI recurrences were common risk factors, emphasizing the need for effective microbiota-based preventive strategies in these patients.

RBL, FDA-approved in November 2022 as the first microbiota-based product for rCDI prevention in adults, is administered rectally after standard-of-care antibiotics. The study population had a median age of 74 years and a median Charlson comorbidity score of 4, with over half having three or more prior CDI recurrences. Risk factors were prevalent, including advanced age (72%), gastric acid suppressant use (55%), immunocompromise (24%), and recent non-CDI antibiotic exposure (21%).¹

All patients received prior antibiotics, most commonly fidaxomicin (58%), before RBL administration. Adverse events were minimal, limited to minor leakage in 5 patients. Age ≥65 was significantly associated with higher recurrence risk. Among patients experiencing recurrence within 8 weeks, median time to relapse was 28 days. Of 30 patients with 6-month follow-up data, 26 (87%) sustained treatment response.¹

These data provide important evidence for clinicians managing complex rCDI cases, highlighting RBL as a valuable and well-tolerated intervention to reduce recurrence risk in routine practice.¹

In relation to RBL, in a recent interview with Paul Feuerstadt, MD, FACG, AGAF, he emphasized that beyond effectively reducing recurrent Clostridioides difficile infections, the treatment plays a crucial role in improving patients’ overall quality of life. Feuerstadt described how recurrent CDI often leads to significant anxiety, fear, and social isolation, likening the emotional burden to post-traumatic stress. He noted that RBL not only targets the infection but also helps restore patients’ mental, physical, and social well-being, allowing them to regain confidence and normalcy in their daily lives.²

Reference

1.Seo S, Hengel R, Krishnan S, et al. Real-World Experience with Fecal Microbiota Treatment (live-jslm) for the Prevention of Recurrent Clostridioides difficile Infection. Abstract 85 E. MAD-ID Meeting. May 28–31, 2025. Orlando, FL.

2.Improved Symptoms and Health-Related Quality of Life in Adults with Recurrent Clostridioides Difficile Infection after Fecal Microbiota, Live-jslm (RBL) Administration by Colonoscopy. Abstract presented at DDW 2025, May 3-6, 2025. Accessed July 1, 2025.

This study investigates the effectiveness of a vitamin D3-loaded nanoemulsion in improving the core symptoms of autism spectrum disorder (ASD) in children. Children with ASD often have low vitamin D3 levels, which are linked to delays in language development, adaptive behavior, and fine motor skills. While traditional vitamin D3 supplementation has shown mixed results in past studies, this research evaluates whether a nanoemulsion form-engineered to enhance absorption and bioavailability-might produce better outcomes.

Eighty children between the ages of 3 and 6 with diagnosed ASD were randomly assigned into two groups: one receiving the vitamin D3 nanoemulsion, and the other receiving a standard marketed vitamin D3 product, both for a duration of 6 months. Their vitamin D3 levels, adaptive behaviors, and language abilities were assessed before and after supplementation using standardized tools such as the Childhood Autism Rating Scale (CARS), Vineland Adaptive Behavior Scale, and Preschool Language Scale. Only the nanoemulsion group showed statistically significant improvements in vitamin D3 levels, autism severity, social IQ, and both receptive and expressive language performance. The conventional supplement, despite raising blood vitamin D3 levels, did not lead to meaningful improvements in behavioral outcomes.

The study concludes that the nanoemulsion form of vitamin D3 is superior to the conventional oral form in terms of increasing vitamin bioavailability and producing clinically relevant improvements in children with ASD. The authors suggest that nanoemulsion technology could offer a valuable strategy for enhancing the effectiveness of nutritional interventions in neurodevelopmental disorders. However, they acknowledge that further studies with larger sample sizes and long-term follow-up are needed to confirm these findings and explore potential gender-related differences in response.