Exploring optimal pharmacotherapy after bariatric surgery: where two worlds meet Yska, Jan Peter

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1 University of Groningen Exploring optimal pharmacotherapy after bariatric surgery: where two worlds meet Yska, Jan Peter IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Yska, J. P. (2017). Exploring optimal pharmacotherapy after bariatric surgery: where two worlds meet [Groningen]: Rijksuniversiteit Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 3 CHAPTER INFLUENCE OF BARIATRIC SURGERY ON THE USE OF MEDICATION Jan Peter Yska Douwe H. van der Meer Albert R. Dreijer Willeke Eilander Jan A. Apers Marloes Emous Erik R.E.Totté Bob Wilffert Eric N. van Roon Published in: European Journal of Clinical Pharmacology 2016;72:203-9.

3 ABSTRACT Purpose Bariatric surgery can influence the prevalence and incidence of comorbidities, as well as the pharmacokinetics of drugs. This might lead to changes in the use of drugs. This study aimed to assess the influence of bariatric surgery on the use of medication in patients before and after surgery, focusing on type, number of medications, and daily dosage. Methods In a retrospective and prospective observational study, drug dispensing data from pharmacies of patients undergoing their first bariatric surgery between January 2008 and September 2011 was collected. Dispensing data from 1 month before until 12 months after surgery was analyzed. Drugs were classified according to the WHO- ATC classification system. Dosages of drugs were compared using defined daily dose (DDD). Results Among 450 patients 12 months after surgery, the mean number of drugs per patient for antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs, and drugs for obstructed airway diseases decreased by, respectively 71.3 % (95 % CI 57.2 to 85.4), 34.5 % (95 % CI 28.2 to 43.0), 45.5 % (95 % CI 13.3 to 72.6) and 33.1 % (95 % CI 15.3 to 53.2). Patients used lower median DDD of oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. Conclusions For some major drug classes 12 months after bariatric surgery, the use of drugs decreases in terms of mean number per patient. A reduction in dose intensity was observed for oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. Dispensing data from pharmacies may provide detailed information on the use of medications by patients after bariatric surgery. 42

4 INTRODUCTION Obesity has become a major global health problem. Managing obesity by diet, physical exercise, or behavioral therapies has very limited success in achieving longterm weight loss. Pharmacotherapy for obesity is characterized by safety issues and lack of high-quality evidence for efficacy from long-term studies [1]. Bariatric surgery is the only medical intervention for morbid obesity that has been shown to produce long-term weight loss [2]. Patients undergoing bariatric surgery have excess weight, often accompanied by multiple comorbidities, such as type 2 diabetes mellitus, cardiovascular diseases, obstructive sleep apnea, osteoarthritis and depression. For those comorbidities, patients may use various medications. Bariatric surgery can influence the prevalence and incidence of comorbidities [3]. Moreover, after bariatric surgery, drug absorption may be reduced leading to alterations in pharmacokinetic parameters [4]. Literature on the influence of bariatric surgery on the pharmacokinetics of drugs is sparse [5]. However, several studies on the use of medication after bariatric surgery have been published [6-13]. The improvement or resolution of comorbidities, as well as the effects on pharmacokinetics of drugs, might lead to changes in pharmacotherapy. The use of medication may be continued or stopped, and the dosage or dosage form may be changed after bariatric surgery. So far, a reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes [6-8,10,11,13]. Those studies compiled data from an administrative database of a large managed care organization [7], claims data from health plans coverage [8], reimbursement claims for outpatient prescription medication dispensing records [10], hospital s electronic medical record [12,13], medical chart review [6] or pharmacy benefits management data [11]. Some studies did not distinguish between the different types of surgical procedures [8,10,11]. In other studies on medication use after bariatric surgery, only data from patients after gastric bypass was analyzed [6,7,12]. Nonetheless, we believe original data from dispensing pharmacies with details on the dosing of medication has not been used to date in drug utilization studies after different types of bariatric surgery. 3 The aim of the present study was to examine changes in the use of medications after bariatric surgery, focusing on medication type, number, as well as daily dosage. 43

5 METHODS Data Acquisition This retrospective and prospective observational study explored the use of medication of patients undergoing their first bariatric surgery in Medical Centre Leeuwarden from January 2008 to September The Regional Review Board waived this study from review as Dutch legislation does not require this for studies that do not affect the patient s integrity. After having obtained written informed consent, demographic data were gathered from the Department of Surgery of the hospital. These data included age, gender, type of bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy, gastric banding, mini gastric bypass or Scopinaro), date of surgery, and body mass index (BMI) before and 1, 6, and 12 months after surgery. Medication dispensing data, including medication dosage formulation, daily dosage, and total number supplied from 1 month before until 12 months after surgery were collected from the patient s pharmacies. All demographic data and dispensing data of medication were entered in an Access database (Microsoft ). Patient data were anonymized. Retrospective data were collected from patients who had already undergone bariatric surgery; prospective data were gathered from patients undergoing bariatric surgery. This is a naturalistic study: during the study period, no active intervention was carried out to change drug use from routine. Analysis Based on the dispensing data, for each patient, the use of medication expressed as the number of different medications used per day was determined on the day of surgery and 1, 6, and 12 months after surgery. Medications on the day of surgery did not include surgery-related medications. In the database, drugs were linked to their codes from the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC) classification system. In this way, it was possible to analyze the use of medication according to ATC groups. The ATC system also includes defined daily doses (DDDs) for the majority of drugs [14]. According to the definition, DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults [15]. Dosages of different medications from the same ATC group could be compared by correcting for the DDD. In case of using several drugs from the same ATC group, DDDs were added up. ATC level 1 main groups with drugs used by >5 % of the patients on the day of surgery were selected for further analysis of medication use. For each group, the number of medications used on the day of surgery and 1, 6, and 12 months after surgery was determined. Medication use is reported as the mean number of medications per 44

6 patient with distinction between restrictive-malabsorptive and restrictive types of surgery. Therapeutic (level 2) and pharmacological (level 3) ATC subgroups with drugs used by >15 % of the patients on the day of surgery were identified for further analysis of medication use. Use of some ATC level 2 and level 3 subgroups of special interest, because bariatric surgery or weight loss might affect the use of these drugs, was also studied. For each level 2 and level 3 subgroup, medication number and dosage were obtained on the day of surgery and 1, 6 and 12 months after surgery. In addition, median daily dosage per patient was determined at each time point from the ATC subgroups. Statistical Methods For comparing the mean number of medications per patient on the different time points, Poisson regression with generalized estimating equations (GEE) was used. This analysis method considers longitudinal repeated measures. The p values were twosided and statistical significance was considered when p<0.05. All statistical analyses were performed using SPSS version 20.0 (IBM Corp., Armonk NY). SPSS was also used for determining median daily dosage and making boxplots for DDD. 3 RESULTS This study included 450 patients (Table 1). Data were collected retrospectively from 256 patients and prospectively from 194 patients. Ninety-one of the patients were male (20.2 %). Mean age was 43.4±10.1 years. Surgical procedures included Roux-en-Y gastric bypass (74 %), sleeve gastrectomy (15 %), gastric banding (7 %), mini gastric bypass (1 %) and Scopinaro (3 %). The mean BMI decreased from 44.8±6.7 kg/m² presurgery to 31.3±5.6 kg/m² 12 months after surgery. The results for use of all medications and for medication from some major ATC level 2 and level 3 classes are shown in Table 2 as mean number of drugs per patient. Among 450 patients, the mean number of medications per patient decreased from 3.66 on the day of surgery to 3.25 at 12 months after surgery (p<0.05). After a restrictivemalabsorptive procedure (Roux-en-Y gastric bypass, minigastric bypass) the mean number of medications per patient decreased from 3.91 on the day of surgery to 3.40 at 12 months after surgery (p<0.05). Patients who underwent a restrictive weight loss procedure (gastric banding, sleeve gastrectomy) used less medication at the day of surgery (2.78) than patients who underwent a restrictive-malabsorptive procedure and did not show a significant decrease in use of medication 12 months after surgery (2.63). For several ATC level 1 and level 2 classes, the mean number of drugs per patient decreased by more than 10 %: drugs used in diabetes (ATC-class A % (95 % CI 57.2 to 85.4)), drugs acting on the cardiovascular system (ATC-class C 34.5 % (95 % CI 45

7 28.2 to 43.0)), drugs acting on the musculoskeletal system (ATC-class M 33.2 % (95 % CI to 60.1)) and drugs acting on the respiratory system (ATC-class R 26.6 % (95 % CI 13.4 to 44.4)). On the other hand, an increase in the mean number of drugs per patient was seen for drugs acting on blood and blood-forming organs (ATC-class B % (95 % CI 58.7 to 122.8)). By 12 months after surgery, the mean number of medications for patients who underwent a restrictive-malabsorptive procedure showed significant (p<0.05) reductions for insulins and analogs (-71 %), blood glucose-lowering drugs (-72 %), diuretics (-39 %), beta-blocking agents (-25 %), agents acting on the renin-angiotensin system (-47 %), lipid-modifying agents (-23 %), anti-inflammatory and antirheumatic products, nonsteroids (-55 %), antidepressants (-9 %) and drugs for obstructive airway disease (-36 %). For most of these drug classes 1 month after surgery, a prompt reduction in the mean number of medications was already seen (Table 2). On the other hand, for patients who underwent a restrictive procedure 12 months after surgery, the reduction in mean number of medications was not significant for diuretics, beta-blocking agents, lipid-modifying agents, anti-inflammatory and antirheumatic products, nonsteroids, antidepressants and drugs for obstructive airway disease. Drugs for acid-related disorders showed a rise in mean number of medications per patient 1 month after surgery (from 0.34 at surgery to month after surgery), returning to presurgery levels at 12 months after surgery (0.34). The mean number of medications per patient (all procedures) for thyroid replacement medication, analgesics and antidepressants showed no significant decrease. For mineral supplements and vitamin B12, a sharp rise in use was observed (mean number of medication per patient at surgery 0.04 and 0.03; at 12 months after surgery 0.37 and 0.13, respectively (p<0.05 compared with at surgery). For some major ATC level 2 and level 3 classes, the use of medication in the year after surgery is shown in Fig. 1 as the mean number of drugs per patient for all patients, as well as boxplots for DDD for patients using medication. For patients using blood glucose-lowering drugs (excluding insulins), beta-blocking agents and lipid-modifying agents 12 months after surgery reductions in median daily dosage of 37, 6, and 17 %, respectively, were seen. For thyroid replacement medication, a rise of 11 % in median daily dosage was observed 12 months after surgery. No change in median daily dosage was shown for antidepressants and drugs for obstructive airway diseases. 46

8 TABLE 1. Patient characteristics. Restrictive - malabsorptive Restrictive Scopinaro Sleeve gastrectomy Gastric banding Mini gastric bypass Roux-en-Y gastric bypass Characteristic All patients Number of patients (%) 450 (100) 333 (74.0) 15 (3.3) 30 (6.7) 69 (15.3) 3 (0.7) Male (%) Age (yr) 43.4 ± ± ± ± ± ± 6.5 Use of medication on day of surgery (%) BMI (kg/m²) Presurgery (n) 44.8 ± 6.7 (441) 45.4 ± 6.9 (325) 41.0 ± 5.1 (15) 41.3 ± 4.1 (30) 44.2 ± 6.3 (68) 53.3 ± 5.4 (3) 1 month postsurgery (n) 40.2 ± 6.2 (420) 40.7 ± 6.2 (313) 36.4 ± 5.2 (14) 38.0 ± 3.2 (23) 39.7 ± 6.6 (68) 48.6 ± 3.6 (2) 6 months postsurgery (n) 33.9 ± 5.6 (402) 34.0 ± 5.5 (301) 29.8 ± 3.9 (15) 34.9 ± 4.0 (22) 33.9 ± 6.5 (61) 39.7 ± 6.0 (3) 12 months postsurgery (n) 31.3 ± 5.6 (352) 31.1 ± 5.5 (266) 27.2 ± 2.5 (12) 33.7 ± 4.1 (20) 32.0 ± 6.7 (53) 36.2 (1) Data presented as mean ± standard deviation. BMI body mass index. 3 47

9 TABLE 2. Use of medication: mean number of medications per patient per day. at surgery 1 month after surgery RM R T RM R T (n=348) (n=99) (n=450) (n=346) (n=99) (n=448) All medication ( ) ( ) ( ) ( ) ( ) ( ) ATC class A10A Insulins and analogues A10B Blood glucose lowering drugs, excluding insulins C03 Diuretics C07 Beta blocking agents C09 Agents acting on the renin-angiotensin system C10 Lipid modifying agents H03 Thyroid therapy M01A Anti-inflammatory and antirheumatic products, non-steroids N02 Analgesics N06A Antidepressants R03 Drugs for obstructive airway diseases * 0.07* 0.12* ( ) ( ) ( ) ( ) ( ) ( ) * * ( ) ( ) ( ) ( ) ( ) ( ) * 0.19* 0.23* ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) * * ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) * ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) All values with 95% confidence intervals RM restrictive malabsorptive procedures (Roux-en-Y gastric bypass, mini gastric bypass), R restrictive procedures (gastric banding, sleeve gastrectomy), T total (all procedures) *p<0.05 compared with at surgery 48

10 6 months after surgery 12 months after surgery Difference after 12 months at surgery RM R T RM R T for T (%) (n=343) (n=98) (n=444) (n=332) (n=97) (n=431) 3.45* * 3.40* * ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.07* 0.04* 0.07* 0.06* 0.02* 0.05* ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.08* 0.06* 0.07* 0.08* 0.07* 0.08* ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.17* * 0.17* * ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.17* * 0.15* * ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.22* * 0.17* 0.15* 0.16* ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.19* * 0.17* * ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.05* * 0.05* * ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) * ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.22* * 0.18* * ( ) ( ) ( ) ( ) ( ) ( ) ( ) 49

11 FIGURE 1. Use of medication in the year after surgery: mean number of drugs per patient (all patients) as well as defined daily dose for patients using medication from some major ATC subgroups. 50

12 DISCUSSION This study reports a significant reduction of mean number of all medications per patient 12 months after restrictive-malabsorptive weight loss procedures. In contrast, we did not find a significant reduction after restrictive procedures. In a study on bariatric surgery versus intensive medical therapy in obese patients with diabetes, Schauer et al. collected data on use of antidiabetics and cardiovascular medication distinguishing gastric bypass and sleeve gastrectomy patients [13]. After both surgical procedures at 12 months after surgery, they found significant reductions in use of diabetes medication, lipid-lowering agents, antihypertensive agents, agents acting on the renin-angiotensin system, and anticoagulants in comparison to nonsurgical patients. However, in patients with sleeve gastrectomy, reductions in medication use tended to be less pronounced than in patients with gastric bypass. For all patients, a significant reduction in mean number of medications 6 months postsurgery was found. Segal et al. [8] and Crémieux et al. [10] reported changes in medication use at 3 months after bariatric surgery. We report that at 1 month postbariatric surgery, medication utilization is significantly changed. More specifically, the use of antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs (nonsteroids), is changed 1 month after surgery, especially after a restrictive-malabsorptive procedure. The reductions in use of medication from those ATC-classes may suggest a rapid improvement of comorbidities after bariatric surgery starting before maximal weight loss is achieved. 3 After surgery, this study shows a rising use of mineral supplements (calcium), drugs for blood and blood-forming organs (iron, folates, vitamin B12) and drugs for acidrelated disorders (proton pump inhibitors). Nutrient deficiencies may not only occur after malabsorptive procedures but also after restrictive procedures. Therefore, use of vitamins and minerals is recommended after surgery [16, 17]. For drugs for acidrelated disorders, a temporary rise in use is observed 1 month after surgery. This may be caused by protocolized prescription of proton pump inhibitors as prophylaxis for marginal ulceration after Roux-en-Y gastric bypass. As Coblijn et al. showed, there is no consensus in literature on the duration of prophylaxis [18]. The positive effects of bariatric surgery on remission or improvement of type 2 diabetes mellitus are reflected in the decreased use of oral antidiabetics and insulins postbariatric surgery. These results are consistent with prior findings [5,8,10,13,19]. The reduced use of drugs for cardiovascular disease (diuretics, beta-blocking agents, agents acting on the renin-angiotensin system, lipid-modifying agents), nonsteroidal anti-inflammatory drugs, analgesics and respiratory medications after bariatric surgery is comparable with previously reported changes in use of drugs after bariatric surgery [5-8, 10,11]. 51

13 For thyroid replacement medication, this study shows a sustained use after bariatric surgery with a higher daily dosage per patient. So far, data on the effect of bariatric surgery on hypothyroidism and the use of thyroid hormone medication is limited and not consistent [5]. Data from literature on the use and pharmacokinetics of antidepressants after bariatric surgery is limited [5]. For antidepressant use, Segal et al. reported a 9 % decrease 12 months after bariatric surgery [8]. Cunningham et al. found no decrease in the majority of patients after Roux-en-Y gastric bypass [12]. In our study, after all types of surgery, no changes in the use of antidepressants or in the median daily dosage were observed. However, postrestrictive-malabsorptive procedures, a significant decrease in use 12 months after surgery was identified. This is the first study on the influence of different types of bariatric surgery, on the use of medication based upon original complete and detailed dispensing data of all medications from patient s pharmacies, showing changes in medication. This study has several limitations. To explore the use of medications, dispensing data from patient s pharmacies has been utilized. However, there may be a discrepancy between the patient s actual use of medication and the use assessed by dispensing information. Nevertheless, to determine the change in medication use over time, before and after bariatric surgery, dispensing data should be an adequate substitute for the actual use of medication. In this observational study, no information on the reasons for medication discontinuation or for dosage change was collected. Detailed use of over the counter medication was not recorded in this study. Eighty percent of our patient population was female, thus it is difficult to apply our results to men. However, this distribution is an accurate representation of the population undergoing bariatric surgery. Finally, this study had a relatively short duration of follow-up (12 months after surgery). CONCLUSION Bariatric surgery influences the use of medication. For some drug classes, medication utilization rates are shown to be altered in the short-term postsurgical period. Twelve months after surgery, the use of antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs, and drugs for obstructed airway diseases decreases in terms of mean number per patient. However, after restrictive procedures, decreases are less pronounced. Twelve months after surgery, the use of oral antidiabetics, beta-blocking agents and lipid-modifying drugs show a reduction in dose intensity. Dispensing data from pharmacies provide detailed information on the use of medication by patients after bariatric surgery. This information may be used in further research on changes in pharmacotherapy caused by improvement or resolution of comorbidities, as well as altered pharmacokinetics of drugs after bariatric surgery. 52

14 ACKNOWLEDGEMENT We thank NJGM Veeger, PhD, clinical epidemiologist, Medical Centre Leeuwarden, for his statistical help. 3 53

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