The prevalence of obesity has increased over the years, in particular of severe obesity. The category of obesity with body mass index (BMI) ≥ 35 kg/m2
] presented the highest increase among other categories such as overweightness and obesity [2
] and was recorded in 12% of the world population in 2015 [3
]. Obesity culminates with the emergence of other comorbidities [4
], such as the already well-established triad of arterial hypertension (AH) [5
], diabetes mellitus (DM) [6
], and hypercholesterolemia [7
]. In addition, these patients may still have problems related to the renal system [8
], hepatic system [9
], skeletal muscle [10
], and respiratory system, among others [11
]. In general, this leads to a decline in an individual’s health, as well as an increase in expenses and consequent overloading of health systems [12
Drugs are the main therapeutic tools used for the control and treatment of these morbidities [14
]. However, if misused, these drugs can adversely affect the patients [16
] and they have been involved in many death-related incidents arising from monitoring failures, omissions to provide necessary treatments, and potential drug interactions (PDI), among others [16
]. PDI are responsible for therapeutic failures and constitute a safety problem as they are responsible for most of the incidents related to drug use [18
]. For this reason, the World Health Organization urged its signatories to join efforts to reduce deaths associated with drug misuse by 2022 [19
Considering the importance of PDI in drug-related morbidity and mortality [20
], the prevalence and risk factors for its occurrence in groups of patients with acquired immunodeficiency syndrome [21
], elderly [22
], and oncology [23
] is well-established. However, in the obese population, especially among the severely obese, such parameters are not yet known. Pharmacoepidemiological studies involving this group of patients are more related to elucidating pharmacological aspects of obesity treatment as well as new molecules and therapeutic targets [24
]. A study designed to estimate the prevalence of obesity and associated morbidities described the use of anti-hypertensives and lipid lowering drugs, but did not consider other concomitant medications [26
Given the knowledge gap, identification and consideration of the importance of obesity as a public health problem as well as the prioritization of medication safety in world agenda is important. This study aimed to analyze the prevalence of PDI and associated factors in severely obese patients.
150 patients were analyzed and the PDI prevalence was 50% (n
= 75) (95% CI 41–58). Each patient had on average 1.54 PDI (SD ± 0.20, 95% CI 1.13–1.05). Approximately 84% (n
= 63) of PDI were due to the use of non-prescription drugs. A total of 236 pairs of drugs with PDI were analyzed. Regarding the severity of potential drug interactions, most 98.72% (n
= 233) were contraindicated, major and moderate. Among these, the most frequent pairs were ethinylestradiol + caffeine and diclofenac + losartan, with 93.0% (n
= 14) and e 5.08% (n
= 12), respectively. The only contraindicated association observed was between trometamol ketorolac + naproxen (0.42%). Among the major cases, the association with diclofenac + hydrochlorothiazide was the most prevalent, with 10.53%. Among the associations considered as less severe, 10.22% (n
= 14) occurred with ethinylestradiol + caffeine, and 8.76% (n
= 12) with diclofenac + losartan (Table 1
There was no association between PDI and socio-demographic variables and lifestyle (Table 2
). A statistically significant association was observed between the health and medication use variables and the occurrence of PDI with hypertension, diabetes, number of self-reported morbidities, use of drugs that cause weight gain, and polypharmacy (Table 3
). After the multiple analyses by Poisson regression, the variables that remained associated with the occurrence of PDI were hypertension (PR 1.83, 95% CI 1.10–3.04), polypharmacy (PR 3.12, 95% CI 2.17–4.50), and diabetes (PR 0.60, 95% CI 0.45–0.81) (Table 4
* Pearson’s Chi-square, ** Linear trend Chi-square, 1 n = 84.
The therapeutic classes most associated with occurrence of PDI were alimentary tract and metabolism (p
< 0.001), blood and blood forming organs (p
= 0.005), cardiovascular system (p
< 0.001), systemic hormonal preparations, excluding sex hormones and insulin (p
= 0.001), and musculoskeletal system (p
< 0.001) (Table 5
According to the literature, this is the first study to evaluate the drug use profile in severely obese patients associated with the occurrence of PDI and other variables on health conditions. It is increasingly relevant to know the health aspects and risks in severe obesity, since obesity is the fastest growing health condition in the world [1
], and the one of greatest risk of aggravations and consequent mortality. The presence of PDI was elevated among the severely obese in association with other morbidities such as diabetes and hypertension, in addition to polypharmacy. Obesity and the morbidities associated with obesity, such as hypertension and diabetes [6
], demand the use of more drugs, leading the patient to polypharmacy, which further increases the likelihood of occurrence of PDI. Our study demonstrated that polypharmacy increased the risk of the severely obese patient presenting PDI more than three-fold.
Although previous studies related to the prevalence of PDI in severely obese individuals are not available, such outcomes have been described in studies on patients with chronic health conditions [22
]. The prevalence of PDI in the present study was higher than observed in a study with the elderly (36.9%) [22
], and less than in onco-haematological patients (71.3%) [23
]. This variability in prevalence may occur due to differences between patient/morbidity, study sites, and countries [43
]. These findings reinforce the need for further studies regarding drug use in the severely obese, to establish the patterns of use and therapeutic classes more associated with PDI and their clinical relevance.
In our study, the association with AH and PDI was observed. A clinical explanation for this result may be the difficulty of pharmacological control of AH monotherapy in obese individuals [5
]. The achievement of satisfactory blood pressure levels is a problem in clinical practice in obese patients due to the increased activity of the renin-angiotensin system and aldosterone, which decreases the efficacy of pharmacological treatment [5
]. The addition of multiple drugs may be necessary to achieve appropriate blood pressure levels in these patients [3
], which leads to an increased risk of developing PDI.
As in AH, DM treatment is also commonly performed with drug associations [44
], partially explaining the observed association between PDI and DM. Although the pathophysiology associated with refractoriness to pharmacological treatment of DM in the severely obese is still unknown, in some cases, it may be caused by impaired pharmacokinetics and the bioavailability of drugs because of changes in the volume of distribution [45
], the liver [9
], and renal function [46
]. It is suggested that adequate glycemic control may not be achieved due to the exposure of sub-therapeutic doses, which leads to the addition of other drugs to the therapeutic regimen [44
], which, consequently, increases the possibility of the occurrence of PDI.
Polypharmacy is a reality among patients with chronic conditions [47
]. Although necessary, polypharmacy should be done with caution, since it is associated with the occurrence of PDI, as observed in the present study and described in previous studies [48
]. It is known that PDI may be associated with the occurrence of adverse drug reactions [49
], as well as increased hospitalization time [20
]. Although no other research was found addressing polypharmacy and the prevalence of PDI in obese patients, this study’s results are in line with other studies in patients with chronic diseases [21
]. In obese patients, these complications may have more serious consequences, such as the onset of serious adverse reactions and a difficulty in controlling comorbidities.
Although sociodemographic variables have not demonstrated an association with the occurrence of PDI, these results are in line with those of other studies. Sex and age were not associated with the occurrence of PDI in a study conducted in onco-hematological patients [23
] and the institutionalized elderly, as well as the marital status and schooling in the latter case [43
]. The occurrence of PDI in obese individuals seems to be more associated with clinical aspects and morbidities than sociodemographic variables.
The drugs that act in the digestive system and metabolism were associated with the occurrence of PDI, which may be partially explained by the presence of antidiabetics. These drugs’ metabolism is made by the enzymatic systems involved in the metabolism of other drugs, which may result either in therapeutic ineffectiveness or in a safety problem [50
The occurrence of PDI associated with cardiovascular and musculoskeletal system drugs may be partly explained by the influence of non-steroidal anti-inflammatory drugs on the action of antihypertensives. The result of such PDI is already well described in the literature, and it decreases the effects of antihypertensives to control patients’ blood pressure levels [51
]. Since obese patients commonly suffer from back, knee, and ankle pain, among others [10
], therapy with nonsteroidal anti-inflammatory drugs may be necessary [53
]. This is a PDI of clinical importance due to its potential for patient harm. There is evidence suggesting the raise of serum creatinine in patients in the use of NSAIDS [52
] and this is a parameter that must be monitored during concomitant therapy. The raise of serum creatinine may lead to renal failure and consequently may affect blood pressure control [51
]. This is a relevant aspect, especially in the severely obese, because it increases the risk of cardiovascular events [36
]. Healthcare professionals must be aware of the risk and its clinical management to identify the reduction of AH treatment effectiveness.
As a possible limitation of this research we could mention the number of patients and their conduction in a single center. However, we emphasize that the results are consistent and relevant to the field of obesity, especially of the severe obese, with a few studies. Although drug use variables and their statistical analysis were not detailed in the clinical trial protocol, all details on this topic were part of a specific objective of original study and were pre-specified in the protocol approved by the local ethics committee. We highlight that all requirements for good clinical research practices were met and strict quality control criteria and methodological rigor were followed in all stages of the research. This study has great importance for clinical practice, as it is the first to analyze the occurrence of PDI and associated factors in severely obese patients. PDI are a major problem among individuals with severe obesity due to their high prevalence and association with other morbidities. However, PDI are susceptible to prevention and management if they are recognized and monitored, so knowing the factors associated with their occurrence has great importance for health professionals.