Evaluation of multiple drug use in patients with type 2 diabetes mellitus

Abstract

Objective

Multiple drug use (Polypharmacy) is common in Diabetes Mellitus (DM) patients. The purpose of this study was to evaluate the presence of polypharmacy and comorbid conditions in patients with DM.

Method

The sociodemographic data, comorbidity diseases, and prescription records of 607 patients diagnosed with type 2 DM were retrospectively analyzed. Polypharmacy was defined as the use of five or more different drugs.

Results

The mean number of drugs used by the DM patients was 6.7 ± 2.5. It was observed that 77.9% of the DM patients had polypharmacy. The mean number of drugs used by the patients in the polypharmacy group was 7.7 ± 1.7. The most common comorbidities in DM patients were diseases of the musculoskeletal system. The use of drugs for musculoskeletal diseases and the number of drugs were statistically higher in female patients than in male patients. In the DM patients, polypharmacy was higher in the females, those older age, those having a longer history of DM disease, and those having a comorbid disease.

Conclusion

The total number of drugs used by the DM patients showed the presence of polypharmacy. Advanced age, long disease duration, female gender, and presence of comorbidities were predictive factors for polypharmacy in diabetic patients. Before starting additional medication for DM patients, it is necessary to pay attention to the interaction of the drugs to be used and to plan prescriptions considering the medications used by the patient continuously.

Introduction

Today, the number of drug prescriptions is increasing across the world, causing more adverse drug events. This is an important cause of death, illness, and disability which have almost reached the level of a pandemic. The risk of adverse drug events is associated with old age, multiple comorbidities, dementia, weakness, and limited life expectancy, and the major contributor is polypharmacy in this regard. Although our knowledge of polypharmacy has improved over time, it is still a problem for patients [1]. The incidences of polypharmacy were reported to be 41%, 43.4%, 35.8%, and 46.8% in Iceland, USA, Australia, and Italy, respectively [2]. The use of five or more drugs can be considered polypharmacy [3]. Polypharmacy can be classified into two categories. The first refers to appropriate polypharmacy when a patient takes many drugs prescribed based on clinical evidence. The second refers to inappropriate polypharmacy when a patient takes more medication than needed or required [4]. Generally, more than one medication is required to treat chronic diseases. An elderly patient with more than one illness condition such as respiratory disease, diabetes, cardiovascular disease usually have to use more than five medications [5]. In general, the most common group of drugs used by individuals includes antihypertensives, antihyperlipidemic, antidepressants, antidiabetic agents, prescription analgesics, prescription proton-pump inhibitors, anticonvulsants, bronchodilators, and muscle relaxants [6]. In some studies, polypharmacy-related drug reactions have been associated with increased mean hospitalization cost, duration, and mortality risk [7, 8]. A comprehensive drug risk assessment should be performed to identify the adverse effects associated with polypharmacy. If a drug has no therapeutically beneficial effect or clinical indication, it should not be used. Avoiding polypharmacy can lead to better outcomes in elderly patients and may also help improve quality of life [9].

Although differences are observed between countries, polypharmacy is seen in around 40% of those aged over 75 years [10]. Therefore, the effects of polypharmacy on morbidity, mortality, and drug costs should be evaluated. Polypharmacy can have dangerous consequences for the elderly for some reasons. The elderly are at greater risk for adverse drug reactions than younger people due to metabolic changes and reduced drug clearance, and this risk increases with the number of drugs used. Sometimes, when the nonspecific signs and symptoms of drug reactions are misinterpreted as a disease, it can lead to the addition of a new treatment [9].

Diabetes mellitus (DM) is one of the common chronic diseases. The number of diabetic patients in the world increased from 246 million in 2006 to 463 million in 2019. An estimated 4.2 million deaths are caused by diabetes between the ages of 20 and 79 [11]. Comorbid conditions that develop as a result of damage to organs such as eyes, heart, kidneys, nerves, and vessels cause a decrease in the quality of life in elderly diabetic patients [12, 13].

As the duration of DM and comorbid conditions increases, it is seen that patients need more than one drug for their glycemic control. Both factors increase the number of drugs in use and the presence of polypharmacy [14].

Polypharmacy is an important problem for the human health and the economy of countries. Many diseases can cause polypharmacy. Recent studies in different populations of DM patients have shown that the disease prevalence increased in recent years, and so did the number of drugs used. The aim of our study was to determine the factors that may cause polypharmacy and which types of drugs increase in frequency in our series of diabetic patients.

Materials and methods

Participants

Sociodemographic data, presence of comorbid disease, and prescription records of 607 patients diagnosed with type 2 DM who applied to the outpatient clinic between September 2019 and February 2020 were reviewed retrospectively using the hospital database. In this study, which was conducted in an Asian population, the consecutive patient group who applied to the outpatient clinic was selected. The presence of polypharmacy was determined according to the number of drugs used by the patients daily. Polypharmacy was defined as the use of five or more different drugs.

Inclusion and exclusion criteria

The DM patients aged over 18 years were included in the study. Those with an active infection, pregnancy, and missing data were excluded from the study. The drugs used for the treatment of short-term and acute diseases were not taken into account in the study (Fig. 1).

Fig. 1.

The data of 681 people in total were scanned from the records. The group with polypharmacy consisted of 522 people; however, 49 people who did not meet the inclusion criteria were excluded from the study and as a result, 473 people were analyzed in the group with polypharmacy. There were 159 people without polypharmacy; however, 25 people who did not meet the inclusion criteria were excluded from the study and as a result, 134 people were analyzed in the group without polypharmacy

Statistical analysis

IBM SPSS software package (v.22.0, IBM) was used in the statistical data analysis. Average, standard deviation, percentage, maximum and minimum values were used in descriptive statistics. The distribution of variables was evaluated using the Kolmogorov–Smirnov test. Independent sample t test was applied to those with a normal distribution. Chi-square test was used to compare categorical variables. Logistic regression analysis was carried out to determine the factors predicting polypharmacy. Statistical significance was set at p < 0.05.

Ethics committee approval

This study was carried out with the approval of Karabuk University Non-Interventional Clinical Studies Ethics Committee (Approval No: 2020/210, Approval Date: 14/05/2020). As this is a retrospective study, informed consent form was not obtained from the individuals.

Results

607 type 2 DM patients participated in the study. Their mean age was 59.9 ± 9.5 years. The mean number of drugs used by the DM patients was 6.7 ± 2.5 (min: 0—max: 13). The mean number of drugs used by the patients in the polypharmacy group was 7.7 ± 1.7.

60.4% (n = 367) of the participants were female and 39.5% (n = 240) were male. When the number of drugs used by the DM patients were evaluated, it was seen that 77.9% (n = 473) of the patients used five or more drugs and categorized as having polypharmacy (p < 0.001). There was a statistically significant difference between the patients with and without polypharmacy in terms of gender (p = 0.007), age (p < 0.001) and duration of DM (p < 0.001). Polypharmacy was higher in the female gender, older age, having a long history of DM disease. The participants’ mean BMI (Body Mass Index) was 28.5 ± 6.3. The BMI was 29.6 ± 6.5 in the polypharmacy group and 27.8 ± 5.7 in the non-polypharmacy group. The mean number of DM drugs was 2.0 ± 1.7 in the whole group and 2.1 ± 1.6 in the polypharmacy group. The most common comorbid condition in DM patients was musculoskeletal system diseases (n = 443, 81.0%). The group of DM and cancer patients was found to use the highest number of additional medications (8.1 ± 2.8). The rate of polypharmacy in the DM patients was found to be 77.9% (n = 473) (Table 1).

Table 1.

Polypharmacy status according to the sociodemographic characteristics of DM patients and duration of DM

Variables	All patients	Polypharmacy group (≥ 5 drugs)
		Yes	No	p
Number of DM drugs used, mean ± SD	2.0 ± 1.7	2.1 ± 1.6	1.8 ± 1.6	0.072a
Gender, N (%)				0.007b
Female	367 (60.4)	285 (46.9)	82 (53.1)
Male	240 (39.5)	188 (30.9)	52 (69.1)
Age (years), mean ± SD	60.7 ± 9.2	61.6 ± 10.2	55.6 ± 8.1	0.000a
BMI, mean ± SD	28.5 ± 6.3	29.6 ± 6.5	27.8 ± 5.7	0.000a
Occupation, N (%)				0.334b
Not working	288 (47.0)	250 (86.0)	38 (14.0)
Working	319 (53.0)	222 (69.5)	97 (30.5)
Education, N (%)				0.412b
Primary school	211 (34.8)	184 (87.2)	27 (12.8)
Middle school	204 (33.6)	155 (75.9)	49 (24.1)
High school	192 (31.6)	134 (69.8)	58 (30.2)
Residence, N (%)				0.201b
Town	227 (37.2)	165 (72.6)	64 (27.4)
City center	380 (62.8)	308 (81.0)	72 (19.0)
Smoking, N (%)				0.191b
Yes	229 (37.8)	166 (72.4)	63 (17.6)
No	378 (62.2)	307 (81.2)	71 (18.8)
Alcohol use, N (%)				0.271b
Yes	37 (6.0)	20 (54.0)	17 (46.0)
No	570 (94.0)	267 (46.8)	303 (53.2)
Duration of DM (years), mean ± SD	11.2 ± 7.7	12.0 ± 8.5	7.3 ± 3.3	0.000a
Comorbid diseases, N (%)				0.000b
Yes	597 (98.4)	470 (78.7)	127 (21.3)
No	10 (1.6)	3 (30.0)	7 (70.0)
Total, N (%)	607 (100)	473 (77.9)	134 (22.1)	0.000b

N number; SD standard deviation; BMI body mass index

^aIndependent samples test

^bChi-square test

4.5% (n = 24) of the patients received antidiabetic monotherapy, 93.4% (n = 567) with two antidiabetic drugs and 0.9% (n = 6) with three drugs. Among these, 3.9% (n = 24) received insulin, 56.1% (n = 341) Oral Anti Diabetic (OAD), and 38.2% (n = 232) a combination therapy with OAD and insulin. The most commonly prescribed OAD drugs to the type 2 DM patients were metformin with 85.0% (n = 290), sulfonylureas with 34.8% (n = 119), inhibitors of dipeptidyl peptidase-IV (DPP-4 inhibitors) with 29.9% (n = 102), and thiazolidinediones with 10.9% (n = 34). In the type 2 DM patients, the most prescribed insulins were insulin detemir with 37.5% (n = 9) and insulin glargine with 62.5% (n = 15).

According to regression analysis; female gender (Odds Ratio (OR): 2.1, 95% Confidence Interval (CI): 1.3–3.9, p = 0.007), older age (OR: 1.7, 95% CI: 1.1–3.1, p = 0.002), having a longer history of DM disease (OR: 1.4, 95% CI: 1.0–2.6, p < 0.001), and having the comorbid disease (OR: 2.0, 95% CI: 1.2–3.8, p = 0.006) were found to be an independent predictive factor for polypharmacy in DM patients (Table 2).

Table 2.

Logistic regression analysis for the independent predictive factors of polypharmacy

Variables of DM patients	OR	95% CI	p
Female	2.1	1.3–3.9	0.007
Age (years)	1.7	1.1–3.1	0.002
Duration of DM (years)	1.4	1.0–2.6	0.000
Comorbid Disease	2.0	1.2–3.8	0.006

p value, Logistic regression test, gender, age, duration of DM and comorbid disease were included in this regression analysis. OR odds ratio; CI confidence interval

Discussion

Similar to the studies in the literature, the mean number of drugs used by our patients was 6.7 ± 2.5 (min: 0—max: 13). In their study, Silva et al. reported that, in DM patients, the number of medications in use per person was within the range of 0–17 and the mean number of drugs used was 5.2 ± 2.9 [13].

In our study, when the total number of drugs used by the DM patients were evaluated, it was seen that 77.9% (473) of the patients used five or more drugs and categorized as having polypharmacy. In the literature, the incidence of polypharmacy in diabetes patients was reported to be between 56.5% and 57.1% [13, 15]. This rate is lower than the one found in our study. In our study, the average number of drugs used by the patients in the polypharmacy group was 7.7 ± 1.7. DM patients are more prone to polypharmacy. Polypharmacy may be observed as a result of inadequate adherence of DM patients to the recommended treatment, control of DM and comorbidities, increasing DM drug doses or prescribing new drugs. This may also lead to a higher risk of drug interactions [13].

In this study, the most common diabetes medication used by DM patients was OAD (56.1%). While 38.2% of the patients were using OAD and insulin together, 3.9% were using insulin alone. In a study evaluating the optimal glycemic control in the elderly with DM, it was found that success was dependent on patient factors, drugs used to achieve the goal, life expectancy, and patient preferences related to treatment [16]. It is necessary to determine the most appropriate treatment method considering the benefit and harm rate related to the treatment and patient compliance.

In our study, according to the regression analysis; being a woman, being older age, having a longer history of DM disease, and the presence of comorbid disease were found to be an independent predictive factor for polypharmacy. Similar to our results, Naore et al. found that being a woman, a longer history of diabetes, and having more complications were significantly associated risk factors with polypharmacy. Similar to our study, in the literature, there are some publications showing that the female gender is associated with multiple drug use [13, 15]. Studies have shown that women are more concerned about their health and want to access health care services more often than men [17, 18]. These concerns, which are more prevalent in women than in men, may further increase the already existing use of multiple drugs in female DM patients.

In our study, it was seen that the number of drugs used by diabetics increased with increasing age and duration of DM. In advanced ages, the increase in chronic diseases causes multiple drug use [3]. As shown in Table 1, it can be predicted that elderly patients suffer more from comorbidities and therefore, they use more drugs. The incidence of polypharmacy was reported to be 84% in elderly patients with diabetes [19, 20]. In a meta-analysis examining the relationship between polypharmacy and negative health outcomes in elderly type 2 DM patients, a relationship was found between polypharmacy and mortality, myocardial infarction, stroke, and hospitalization. These findings indicate that interventions are needed to balance benefits and harms in drug prescribing [21]. Some studies have shown that polypharmacy among patients with diabetes is important because polypharmacy increases the probability of adverse drug events, duplication of therapy and leads to a suboptimal glycemic control, increased risk of hospitalization, poor quality of life, high healthcare cost, and ultimately, a higher mortality rate [22–24]. In addition, in some studies, it was found that polypharmacy caused a significant increase in rehospitalization after discharge [25, 26].

An important factor contributing to the increase in the number of drugs in use is the increase in comorbidity conditions [27]. It was observed that the rate of drug use and the number of drugs used for musculoskeletal diseases were higher in female DM patients than in males. This group generally consisted of elderly patients and might have used anti-inflammatory drugs more frequently due to reasons such as neuropathy, osteoarthritis, and degenerative arthritis. In a study conducted on diabetic patients, the incidence of polypharmacy was found to be three times more in the presence of musculoskeletal disease compared to other comorbid diseases [22]. In our study, the participants’ mean BMI was 28.5 ± 6.3. BMI was found to be the highest in musculoskeletal diseases among comorbid diseases (34.2 ± 5.0). This result suggests that weight gain in diabetic patients may lead to an increase in musculoskeletal disorders. Previous studies have shown that DM patients frequently use additional drugs related to the cardiovascular system, nervous system, and digestive system [28–30].

The group of DM and cancer patients was found to use the highest number of additional medications. Cancer may cause many different system symptoms in patients [31]. We are of the opinion that additional drug use is more common in DM patients with cancer due to the premedication used to prevent side effects of chemotherapeutics, such as narcotic and non-narcotic analgesics, antihistamines, antiemetics, antacids, and prophylactic antibiotics.

Our study has some limitations. In Turkey, patients with type 1 DM were generally treated and followed up in endocrinology outpatient clinics, so this group of patients was not included in our study. Another limitation of our study is that there is not enough information about the toxicities (laboratory changes, objective clinical side effects, etc.) that may have occurred due to polypharmacy. Another limitation of our study is that it is a single-center study.

Conclusion

In this present study, it was determined that polypharmacy was high in the DM patients who applied to our clinic. Advanced age, long disease duration, female gender, and comorbidities were found to be predictive factors for polypharmacy in diabetic patients. Before starting additional medication for DM patients, it is necessary to look at the interaction of the drugs to be used and to plan prescriptions considering the medications used by the patient continuously.

Author contributions

All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Funding

The authors declared that this study received no financial support.

Compliance with ethical standards

Conflict of interest

No conflict of interest was declared by the authors.