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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 6
| Issue : 3 | Page : 167-172 |
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Differences in muscle strength, physical activity, and cardiometabolic risk factors between type 2 diabetic patients with and without benzodiazepines or antipsychotic medications
Hidetaka Hamasaki
Hamasaki Clinic, Kagoshima, Japan
| Date of Submission | 07-Jun-2022 |
| Date of Acceptance | 11-Aug-2022 |
| Date of Web Publication | 30-Sep-2022 |
Correspondence Address:
Dr. Hidetaka Hamasaki
Hamasaki Clinic, 2-21-4 Nishida, Kagoshima 890-0046
Japan
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_14_22
Objective: This study aimed to examine differences in muscle strength, physical activity, and cardiometabolic risk factors between Type 2 diabetic patients with and without benzodiazepines (BZD) or antipsychotic drugs (APD). Methods: The author conducted a cross-sectional study on patients with Type 2 diabetes (T2D) whose medication history was collected, and handgrip strength (HGS) was measured. Non-BZD- or APD-users were matched one-to-one with the BZD- or APD-users with respect to their age, gender, and body mass index. The differences in HGS, physical activity, and cardiometabolic risk factors such as blood pressure, lipid profile, and glycemic control between groups were assessed. Results: One hundred and ninety-six patients with and without BZD and 85 patients with and without APD were enrolled. HGS and walking time were significantly lower in patients treated with BZD or APD users than those without BZD or APD. Serum triglycerides levels were higher and high-density lipoprotein cholesterol levels were lower in patients treated with APD than those treated without APD. Both BZD and APD users had a longer sleep duration than nondrug users. Conclusion: BZD and APD were associated with decreased muscle strength and daily physical activity, and APD could impair lipid metabolism in patients with T2D, which may result in increasing the risk of cardiovascular (CV) events. BZDs and APDs should be judiciously prescribed for patients with T2D who are at high risk of CV disease.
Keywords: Antipsychotic drug, benzodiazepine, cardiometabolic risk, handgrip strength, physical activity, Type 2 diabetes
How to cite this article:
Hamasaki H. Differences in muscle strength, physical activity, and cardiometabolic risk factors between type 2 diabetic patients with and without benzodiazepines or antipsychotic medications. Heart Mind 2022;6:167-72 |
How to cite this URL:
Hamasaki H. Differences in muscle strength, physical activity, and cardiometabolic risk factors between type 2 diabetic patients with and without benzodiazepines or antipsychotic medications. Heart Mind [serial online] 2022 [cited 2023 Mar 29];6:167-72. Available from: http://www.heartmindjournal.org/text.asp?2022/6/3/167/357541 |
| Introduction | |  |
Many patients with Type 2 diabetes (T2D) have anxiety, depression, eating disorders, and serious mental illnesses, such as schizophrenia.[1] Adequate treatments for mental illness reportedly also improve the management of patients with T2D.[1] Medical doctors often encounter patients with T2D receiving psychotropic drugs, including benzodiazepines (BZDs) and antipsychotic drugs (APDs), in clinical practice. Indeed, the prevalence of T2D is approximately 10% in patients with schizophrenia, which is higher than that of the general population (8.6%),[2] and patients with schizophrenia also have a higher relative risk (2.5 times) of developing diabetes than healthy individuals.[3] In addition, patients with schizophrenia receiving high-dose BZD exhibit an increased risk of mortality (hazard ratio [HR] = 1.74; confidence intervals [CIs], 1.50–2.03),[4] and use of APD in combination with BZD is associated with an increased risk of mortality (HR = 2.19; 95% CI, 1.83–2.63) in patients with dementia.[5] However, the relationship between BZD or APD use and cardiovascular (CV) disease is controversial.[6],[7],[8] Although the cardiometabolic risk factors, including obesity, hyperglycemia, and dyslipidemia, are significant predictors for CV events, such risk factors are not sufficiently monitored in patients with mental illness who are receiving APD.[9] To the best of our knowledge, no study has examined the difference in the cardiometabolic risk factors between T2D patients with and without BZD or APD use. Moreover, APD use decreases the physical activity level, cardiorespiratory fitness level, and body balance function.[10] A systematic review and meta-analysis reported that the use of APD and BZD was associated with a higher risk of falls (HR = 1.54; 95% CI, 1.28–1.85 and HR = 1.42; 95% CI, 1.22–1.65, respectively).[11] Moreover, patients with T2D have a lower physical activity level,[12] muscle strength,[13] and cardiorespiratory fitness level.[14] Thus, patients with T2D who are receiving BZD and/or APD are particularly physically weak and at high risk for developing comorbidities as compared with those not receiving BZD and/or APD. The present study aimed to investigate the differences in muscle strength, physical activity level, and cardiometabolic risk factors including blood pressure, blood glucose, and lipid profile between T2D patients with and without BZD or APD use, and to discuss the relationship between muscle strength, physical activity, and cardiometabolic risk factors and the use of BZD or APD in patients with T2D.
| Methods | | |
Study design
This cross-sectional study analyzed patients with T2D who were treated at the National Center for Global Health and Medicine Kohnodai Hospital between April 2013 and December 2015. A total of 1327 patients with T2D whose medical history (i.e., regular treatment with BZD and APD) was collected at the first examination were included in this study. Patients aged <20 years, with other types of diabetes, such as T2D, and without medical information were excluded from the analyses. All data were collected anonymously, and data entry was performed by clinical research clerks to avoid potential biases. The study protocol was approved by the Medical Ethics Committee of the National Center for Global Health and Medicine (Reference No. NCGM-G-002052) and performed in accordance with the Declaration of Helsinki.
Physical measurements
Height and weight were measured using a rigid stadiometer (TTM stadiometer; Tsutsumi Co., Ltd., Tokyo, Japan) and calibrated scales (AD-6107NW; A and D Medical Co., Ltd., Tokyo, Japan), respectively. Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters squared. Waist circumference was measured in a standing position at the umbilical level at the end of exhalation. Handgrip strength (HGS) was measured twice using a Smedley analog hand dynamometer (No. 04125; MIS, Tokyo, Japan) for each hand in a standing position. The average HGS in kilograms was used in this study. Blood pressure was measured in a seated position using an automatic sphygmomanometer (HBP-9020; Omron Co., Ltd., Tokyo, Japan).
Medical history taking
Trained technicians at the Clinical Research Center asked patients about their history of CV diseases, including cerebral infarction, myocardial infarction, and arteriosclerosis obliterans, medication use including BZD and APD, daily physical activity levels, exercise habits, smoking and drinking habits, sleep duration, and whether periodic health checkup was conducted in addition to the regular medical examination. The Brinkman index (number of cigarettes per day multiplied by the number of years) was calculated to assess the patients' smoking habits.[15] Regular exercise time per day was calculated by exercise sessions per day multiplied by exercise duration per session. Alcohol consumption was estimated based on the type of alcoholic drink consumed and the number of drinks consumed per day.
Blood assessments
We measured the plasma glucose and hemoglobin A1c (HbA1c), serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol levels at the time of enrollment. The estimated glomerular filtration rate was also calculated using the revised equation adjusted for the Japanese population.[16]
Statistical analysis
Patients without BZD or APD whose age, sex, and BMI were matched to cases (1:1) were enrolled and served as controls. As a result, this study enrolled two age-, sex-, and BMI-matched cohorts, comprising (1) 196 patients with BZD and 196 patients without BZD and (2) 85 patients with APD and 85 patients without APD. Continuous and categorical variables (sex, history of CV diseases, and whether taking periodic health checkup or not) were expressed as the mean ± standard deviation and numbers, respectively. Student's t or Mann–Whitney U-test, depending on the normality test results (Shapiro–Wilk test), was performed to detect statistically significant differences between patients with BZD or APD and those without BZD or APD, as appropriate. Chi-square test was also performed to identify significant differences in categorical variables between groups. P < 0.05 determined by a two-sided test were considered statistically significant. All statistical analyses were performed using SPSS version 25 (IBM Co., Ltd., Chicago, IL, USA).
| Results | | |
Two groups of patients with and without BZD or APD were well-matched for age, sex, and BMI. Our study findings revealed that muscle strength and physical activity level were significantly lower in patients treated with BZD or APD than those not taking BZD or APD. In addition, patients treated with APD had a favorable serum lipid profile compared with those not treated with APD. The HGS was weaker, walking time was shorter, and plasma HbA1c level was lower in patients treated with BZD than in those not taking BZD. Sleep duration was longer in patients treated with BZD than in those not taking BZD [Table 1]. Contrarily, HGS was weaker, alcohol consumption was lesser, walking time was shorter, and HDL-cholesterol level was lower in patients treated with APD than in those not taking APD. In contrast, sleep duration was longer and serum triglyceride level was higher in patients treated with APD than in those not taking APD [Table 2]. No statistically significant difference in the history of CV diseases was observed between patients with and without BZD or APD use; however, the rate of taking periodic health checkups in addition to regular medical examination was lower in patients treated with BZD than in those not taking BZD. | Table 1: Differences in the demographic, physiological, and biochemical data between patients with and without benzodiazepine use
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 | Table 2: Differences in the demographic, physiological, and biochemical data between patients with and without antipsychotics
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| Discussion | | |
The present study examined the differences in muscle strength, physical activity level, and cardiometabolic risk factors, including blood pressure, glycemic control, and lipid profile, between T2D patients with and without BZD or APD use. The author demonstrated that both BZD and APD users had weaker HGS, shorter walking time, and longer sleep duration than those not taking BZD and APD. Furthermore, the plasma HbA1c levels and rate of taking periodic health checkups were lower in BZD users than in non-BZD users, whereas, the serum triglyceride levels were higher and the serum HDL-cholesterol levels were lower in APD users than in non-APD users. To the best of our knowledge, this is the first study to demonstrate that BZD or APD use was significantly associated with muscle strength, physical activity, and cardiometabolic risk factors in patients with T2D.
As it is well known, BZDs are used as skeletal muscle relaxants as well as hypnotics, sedatives, and anxiolytics.[17] Nowak et al.[18] showed that the treatment with APD could probably be a cause of deficits of grip force performance in patients with schizophrenia. In addition, HGS may be a physical indicator of psychotic progression because HGS was negatively correlated with the severity of psychotic symptoms in patients with schizophrenia.[19] Considering that medications for mental illness are intensified as the clinical symptoms worsen, the use of BZD or APD itself should be associated with the decline in HGS. However, the finding that patients treated with BZD or APD had weaker HGS in this study cannot be explained by such drug effects alone. Although there was no difference in the regular exercise time between patients with and without BZD or APD use, daily walking time was significantly shorter in patients taking BZD or APD than in those not taking BZD or APD. We have previously showed that nonexercise activity thermogenesis, defined as daily physical activity except volitional exercise, was also significantly lower in patients with T2D accompanied by mental illness than in those without mental illness.[20] Dopamine is a critical mediator in the regulation of daily physical activity;[21] thus, APD with an antidopaminergic effect could decrease the daily walking time. These findings suggest that both BZD and APD have a negative impact on physical activity, which results in a lowering of skeletal muscle strength. Furthermore, BZD or APD with an anticholinergic effect may lower the HGS in older adults.[22] APD use also potentially increases the serum creatinine kinase levels and is associated with the development of rhabdomyolysis,[23] suggesting that APD has a harmful effect on skeletal muscle. The effect of BZD and APD may be “double-edged sword” (improve mental health but reduce the physical fitness level). Besides, there is a possibility that weaker muscle strength itself is associated with the incidence of psychiatric disorders, which require treatment with BZD or APD. Recently, Cabanas-Sánchez et al.[24] reported that 5 kg lower HGS was associated with a 7% and 8% increased risks of the incidence of depression and anxiety, respectively. The mechanisms underlying the relationship between HGS and psychiatric disorders are unknown; however, some hypotheses could be formulated. Higher HGS was associated with a larger hippocampal volume and a reduction in white matter hyperintensities in patients with mood disorders.[25] The basolateral amygdala and related brain regions including the hippocampus regulate cognition, emotion, and stress.[26] Therefore, the skeletal muscle may play a role in regulating emotional processes and responses to stress via, for example, brain-derived neurotrophic factors.[27] The study design limits inferences of causality; however, muscle strength may be interactively associated with the development of psychiatric disorders.
It is natural that sleep duration was longer in patients treated with BZD and APD because these medications modulate histamine and muscarinic cholinergic receptors.[28] However, the average sleep duration in each group was 7.7 and 7.8 h, respectively, which appeared to have no influence on the incidence of CV events and mortality.[29]
The increase in triglyceride levels and the decrease in HDL cholesterol levels in patients treated with APD are consistent with the results of previous studies. The HDL-cholesterol level was significantly decreased in overweight Japanese patients treated with risperidone, olanzapine, or aripiprazole monotherapy.[30] A recent systematic review showed that the triglyceride level was significantly increased by short-term treatment with olanzapine.[31] Dyslipidemia is a significant risk factor for CV events; therefore, clinicians should pay careful attention to the lipid profile of patients treated with APD.
Intriguingly, the plasma HbA1c levels were lower in BZD users than in non-BZD users; however, this finding should be carefully discussed. HbA1c is a useful and reliable indicator for chronic glycemic control; however, as HbA1c levels reflect the average glucose levels for 1–2 months, glycemic variability, i.e., short-term hypoglycemia and hyperglycemia, cannot be evaluated. The plasma HbA1c levels might be decreased by repeated hypoglycemic events, and HbA1c alone may not show real glycemic control. The underlying mechanism has not been elucidated; however, BZD use may be associated with the occurrence of hypoglycemia. The activation of gamma-aminobutyric acid type A (GABAA) due to BZD administration leads to decreased muscle sympathetic nerve activity and counterregulatory responses to hypoglycemia, including secretion of growth hormone.[32],[33] We cannot explain why patients treated with BZD had lower HbA1c levels than those not taking BZD for certain based on the findings of the present study alone; however, patients treated with BZD could experience hypoglycemia more frequently than those not taking BZD. Hypoglycemia is also a crucial risk factor for CV events and mortality in patients with T2D.[34] Further research is required in the future.
The difference in the rate of taking periodic health checkups between patients with and without BZD use is also interesting. Periodic health checkups are performed voluntarily and separately from regular medical examinations in patients with T2D in Japan; therefore, the rate of taking periodic health checkups may reflect the level of health awareness and literacy among patients. Indeed, the inappropriate use of BZD is partly due to the patients' lack of knowledge about the side effects of BZD.[35] We cannot refer to the health outcomes owing to the lower rate of BZD users taking periodic health checkups; however, medical doctors who usually prescribe BZD should confirm whether their patients adequately understand the therapeutic and side effects of the drug.
In this study, some demographic factors, for example, socioeconomic and educational statuses that affect alcohol consumption were not investigated; thus, the reason for the difference in alcohol consumption between patients with and without BZD use remains unclear. However, previous studies have reported that olanzapine and quetiapine decreased alcohol consumption and alcohol craving,[36],[37] which may explain why patients treated with BZD drink less alcohol.
The present study has several limitations. First, the specific mental illness was not investigated; thus, the association of muscle strength, physical activity, and cardiometabolic risk factors with mental illness treated with BZD or APD, including sleep disorders, anxiety disorders, and schizophrenia are unknown. Second, the number and dose of drugs were not investigated either; thus, whether there is a dose-response relationship between BZD or APD use and HGS, walking time, sleep duration, lipid profile, HbA1c levels, and alcohol consumption is unknown. Despite these limitations, the present study shows that BZD or APD use is significantly associated with muscle strength, physical activity, and cardiometabolic risk factors in a T2D population by analyzing age-, sex-, and BMI-matched cohorts.
| Conclusion | | |
BZD and APD use could decrease muscle strength and daily physical activity, and APD could impair the lipid metabolism in patients with T2D. Skeletal muscle loss, physical inactivity, and dyslipidemia are significant risk factors for CV diseases and mortality; therefore, such risk factors in patients treated with BZD or APD should be carefully monitored in clinical practice. The findings of the present study suggest that clinicians should judiciously prescribe BZD or APD to patients with T2D.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]
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