University of Groningen
Exploring optimal pharmacotherapy after bariatric surgery: where two worlds meet
Yska, Jan Peter
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EXPLORING OPTIMAL PHARMACOTHERAPY
AFTER BARIATRIC SURGERY:
WHERE TWO WORLDS MEET
Publication of this thesis was financially supported by the MCL Academie, Medical Centre Leeuwarden.
Yska, Jan Peter
Exploring optimal pharmacotherapy after bariatric surgery: where two worlds meet. Thesis Groningen University – with summary in Dutch
Cover and layout design Mirjam Leppers, Persoonlijkproefschrift.nl
Printed by Gildeprint, Enschede, The Netherlands
ISBN 978-90-367-9756-6 (book)
ISBN 978-90-367-9755-9 (digital version)
©2017 Jan Peter Yska
All rights reserved. No part of this book may be reproduced in any form without written permission of the author.
EXPLORING OPTIMAL PHARMACOTHERAPY
AFTER BARIATRIC SURGERY: WHERE TWO WORLDS MEET
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op vrijdag 2 juni om 12.45 uur
door
Jan Peter Yska
geboren op 25 juni 1959 te Weststellingwerf
PROMOTORES
Prof. dr. E.N. van Roon Prof. dr. B. Wilffert
BEOORDELINGSCOMMISSIE
Prof. dr. C.A.J. Knibbe Prof. dr. E.F.C. van Rossum Prof. dr. D.J. Touw
C O N T E N T S
SECTION I INTRODUCTION
Chapter 1 General introduction
SECTION II (PHARMACO)EPIDEMIOLOGY
Chapter 2 Influence of bariatric surgery on the use
and pharmacokinetics of some major drug classes
Chapter 3 Influence of bariatric surgery on the use of medication
Chapter 4 Remission of type 2 diabetes mellitus in patients after
different types of bariatric surgery: a population-based cohort study in the United Kingdom
SECTION III OPTIMIZATION OF PHARMACOTHERAPY
AFTER BARIATRIC SURGERY
Chapter 5 NSAID use after bariatric surgery:
a randomized controlled intervention study
SECTION IV BIOAVAILABILITY OF METOPROLOL
Chapter 6 A gastrointestinal simulation system
for dissolution of oral solid dosage forms before and after Roux-en-Y gastric bypass
Chapter 7 A validated high-resolution accurate mass LC-MS assay
for quantitative determination of metoprolol and
α-hydroxymetoprolol in human serum for application in pharmacokinetics
Chapter 8 Effect of Roux-en-Y gastric bypass on the
bioavailability of metoprolol from immediate and controlled-release tablets: a single oral dose study before and after surgery
11 25 41 57 81 97 113 131
SECTION V CONCLUSIONS AND PERSPECTIVES
Chapter 9 General discussion and future perspectives
APPENDICES
Samenvatting (synopsis in Dutch)
Tot slot
Curriculum vitae
List of co-authors
List of publications related to the thesis
157 173 183 187 189 193
SECTION
I
1
CHAP TER
O B E S I T Y
Worldwide overweight and obesity are a growing problem and prevalence rates are increasing. In 2014, more than 1.9 billion adults were overweight. Of these over 600 million adults were obese. Except for parts in sub-Saharan Africa and Asia globally there are more people who are obese, than underweight [1]. As index to classify overweight and obesity the body mass index (BMI) is used. The BMI is a person’s weight in kilograms divided by his height in metres (kg/m²). The World Health Organization (WHO) classification of the BMI is shown in Table 1. In 2015 half of the Dutch aged 20 years and older were overweight (BMI ≥ 25), more men than women (54.4% versus 46.3%). However, more women than men were obese. In total 13.7% of the Dutch were obese (BMI ≥ 30) [2]. Overweight and obesity are associated with increased risk of a wide range of chronic diseases, such as cardiovascular diseases, type 2 diabetes mellitus, several types of cancer, musculoskeletal disorders (especially osteoarthritis), as well as a reduced life expectancy [1,3]. Strategies to prevent the rising prevalence of obesity have had little effect so far. The cornerstone for treatment of a patient with obesity is a combination of lifestyle or behavioural training, dietary change to reduce energy intake, and an increase in physical activity [4]. However, the success of this approach for sustained weight loss is limited.
As long-term results are lacking, there is no place for pharmacological treatment of obesity. Moreover, in the past several drugs for treating obesity have been withdrawn from the market, because of safety concerns. Currently available drugs such as orlistat, naltrexone-bupropion and liraglutide show a modest weight loss after 1 year of therapy. Nevertheless, for these drugs the balance between efficacy and safety is negative [5-6].
Classification BMI (kg/m2)
Underweight < 18.5
Normal weight 18.5-24.9
Overweight 25.0-29.9
Obesity Class I (obesity) 30.0-34.9
Obesity Class II (severe obesity) 35.0-39.9
Obesity Class III (morbid obesity) ≥ 40.0
B A R I A T R I C S U R G E R Y
For morbid obesity (BMI ≥ 40) bariatric surgery is considered the most effective treatment option. Compared with non-surgical options bariatric surgery results in greater improvement in weight loss and weight associated comorbidities [7]. Five years after surgery BMI loss is in the range of 12 to 17 kg/m² [8]. Current US and European guidelines recommend to consider bariatric surgery for patients who failed to lose weight despite non-surgical treatment, if they have a BMI ≥ 40, or ≥ 35 with one or more obesity-related comorbidities, including cardio-respiratory disease, type 2 diabetes mellitus, severe joint disease, severe psychological problems, etc. [9-10]. Women are more inclined to undergo bariatric surgery than men. Almost 80% of all weight-loss surgery patients are female [8]. In 2013 worldwide nearly half a million bariatric procedures were performed, almost all laparoscopically [11]. In the Netherlands there is a large increase in the number of performed weight-loss surgeries to almost 10,000 in 2015 [12].
For bariatric surgery different surgical options are available. The traditional approach of the achievement of the weight loss effect of bariatric surgery is that bariatric procedures are either restrictive, malabsorptive, or a combination of both.
The most commonly performed bariatric surgery procedures with large variations in the preferred procedure between countries, are:
1. Adjustable gastric band (Figure 1)
In this restrictive procedure an inflatable band is placed around the upper part of the stomach to create a smaller stomach pouch. The band is connected to a subcutaneous port. By using normal saline as a filling solution the diameter of the band can be increased or decreased. The intake of food is limited, creating an earlier sense of satiety [13-14]. This operation is reversible. In the Netherlands this procedure is hardly performed anymore. The rate of reoperation is high and weight loss is substantially less than with other procedures [8].
2. Gastric sleeve (Figure 2)
In this procedure the greater part of the stomach is removed, leaving a thin vertical sleeve or tube with a volume of 100-150 mL. The vertical sleeve gastrectomy is a restrictive procedure. Often this gastric sleeve operation is followed by another operation. For people who are either extremely obese or have health problems that make them ineligible for gastric bypass surgery, the gastric sleeve procedure is an option to help them start losing weight. After a few years, most patients lose enough weight for another bypass procedure, the duodenal switch procedure, for further weight loss [13-14].
3. Roux-en-Y gastric bypass (RYGB; Figure 3)
This restrictive-malabsorptive procedure reduces the size of the stomach to a small pouch with a volume of 30-60 mL. This pouch is attached to the jejunum, bypassing most of the rest of the stomach, the duodenum and the proximal jejunum. The biliopancreatic limb is reconnected via a jejunojejunal anastomosis to facilitate the passage of bile salts and pancreatic enzymes. RYGB achieves weight loss by combining restriction of food intake with malabsorption [13-14].
The field of bariatric surgery is continuously evolving with global and regional trends. RYGB is still the most performed bariatric procedure, but global trends show a decrease in the number of RYGB. Although long-term proof of the efficacy of the gastric sleeve is limited, the number of performed gastric sleeve procedures is rising. The gastric sleeve is the most frequently performed procedure in the USA, Canada and in the Asia-Pacific region. Other procedures, such as the omega loop gastric bypass or single anastomosis gastric bypass, have recently become more popular [11,15].
Although restriction of food intake and malabsorption are of significant importance after a bariatric procedure, the exact mechanism involved in weight loss is not yet clear. The changes in gut hormones, such as ghrelin, leptine, PYY, and GLP-1, may play an important role in appetite suppression and increased satiety in patients after bariatric surgery [16-17].
More than 20% of the patients with morbid obesity have had type 2 diabetes mellitus [18]. Bariatric surgery effectively prevents and treats type 2 diabetes mellitus [19]. Surgical treatment for obese patients may be considered an additional treatment option for the management of type 2 diabetes mellitus [20]. Thus, bariatric surgery is actually more than mere weight loss surgery. Not only anatomical, but also physiological changes may be important for the efficacy of bariatric surgery [17,21]. Therefore, for surgical procedures to treat metabolic diseases, especially type 2 diabetes mellitus, the term metabolic surgery is used [21].
Bariatric surgery is not without risks. Complications, such as anastomotic leakage, ulceration, bleeding, stomal stenosis, vomiting, and reflux may occur. Reoperation may then be necessary. Complications associated with bariatric surgery range from FIGURE 2. Gastric sleeve (reprinted with permission from E.O. Aarts and adapted from [13]).
10% to 17% and reoperation rates approximately 7%. However, mortality associated with bariatric surgery is low (0.08-0.35%) [8]. After RYGB, following meals, patients may suffer from palpitations, lightheadedness, and fatigue. These are symptoms of the dumping syndrome. Early dumping begins within 30 min following a meal and is attributable to bowel distention, gastrointestinal hormone hypersecretion and autonomic dysregulation. Late dumping syndrome occurs 1-3 h postprandially with symptoms of hypoglycemia, perspiration, faintness, and decreased concentration [22]. The dumping syndrome is best prevented by dietary changes. Dietary recommendations include smaller and more frequent meals, separating eating and drinking, and decreasing carbohydrate intake [22].
Morbid obesity has been shown to be associated with a high prevalence of micronutrient deficiency, among others, due to eating behaviour and lifestyle. After bariatric surgery vitamin and mineral deficiencies, including deficiencies of vitamin A,
B1, B12, D, folic acid, calcium and iron are common, especially after malabsorptive and
restrictive-malabsorptive procedures. Postoperatively patients should take life-long daily nutritional supplementation [23].
M E D I C A T I O N U S E A F T E R B A R I A T R I C S U R G E R Y
Patients undergoing bariatric surgery have excess weight accompanied by multidrug use for multiple medical comorbidities. Bariatric surgery significantly ameliorates obesity-related comorbidities, such as type 2 diabetes mellitus, hypertension, angina pectoris, myocardial infarction, dyslipidemia, and sleep apnea [8,24]. This might lead to changes in pharmacotherapy. After bariatric surgery, the use of a drug may be continued or stopped, and the dosage or dosage form may be changed because of adverse drug events or to achieve an optimal therapeutic effect. Specific drug characteristics such as the mechanism of drug absorption (passive diffusion versus uptake or efflux
transport), the molecular size, charge, acid-base status, pKa, lipid solubility, and the
particular mechanism of drug clearance (enteric metabolism, hepatic metabolism and renal excretion) should each be considered when studying pharmacokinetics after bariatric surgery [25-27]. Different surgical procedures may each have specific effects on factors influencing absorption, such as disintegration and dissolution, mucosal exposure, and absorption across the intestine, and therefore the pharmacokinetics of a drug may be changed after bariatric surgery [25]. Moreover, after bariatric surgery the effect on pharmacokinetics may vary in time. Table 2 shows the changes after gastric sleeve or RYGB, that may possibly affect the pharmacokinetics of an orally administered drug. Because bypass procedures reduce functional gastrointestinal length, drug absorption may be reduced; however “intestinal adaptation”, mucosal hypertrophy within the remaining intestine resulting in an increase of absorptive capacity, might counterbalance this [25]. All things considered, a variety of factors may affect the use and pharmacokinetics of drugs after bariatric surgery.
Change Gastric sleeve RYGB
Smaller volume of distribution √ √
Increased gastric pH √ √
Reduced gastric mixing √ √
Reduced exposure to digestive enzymes √ √
Gastric emptying accelerated delayed
Reduced surface area for absorption √
Reduced exposure to metabolizing enzymes and
drugtrans-porters in the intestinal wall √
Reduced exposure to bile acids and altered enterohepatic
recycling √
Shorter intestinal transit time √
TABLE 2. Changes after gastric sleeve or RYGB possibly influencing the pharmacokinetics of an orally administered drug [25-26].
A I M A N D O U T L I N E O F T H I S T H E S I S
The aim of the present thesis is to explore optimal pharmacotherapy after bariatric surgery. By combining knowledge of bariatric surgical procedures and its effects on anatomy and physiology, with pharmacoepidemiology and pharmacokinetics, optimal pharmacotherapy after bariatric surgery may be pursued.
To establish what is already known on this subject, in chapter 2, in the second section of this thesis on (pharmaco)epidemiology, we present a review to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. We conducted a literature search, including literature on the influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics.
Next, the results of two (pharmaco)epidemiological studies are presented. In chapter
3, we performed a combined retrospective and prospective observational study 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. Dispensing data from pharmacies of patients undergoing their first bariatric surgery was analyzed from 1 month before until 12 months after surgery. The objective of chapter 4 was to assess the effect of different types of bariatric surgery in patients with type 2 diabetes mellitus on diabetes remission compared with matched control patients, and the effect of the type of bariatric surgery on improvement of glycemic control and related clinical parameters. This retrospective cohort study was conducted within the Clinical Practice Research Datalink (CPRD). The CPRD consists of the computerized medical records of 10 million patients under the care of general practitioners in the United Kingdom.
The third section of this thesis contains the results of a study to optimize pharmacotherapy after bariatric surgery. In chapter 5, we performed a randomized controlled intervention study to determine the effect of an, compared to care-as-usual, additional intervention to reduce nonsteroidal anti-inflammatory drug (NSAID) use in patients who underwent bariatric surgery, and to determine the use of proton pump inhibitors in patients who use NSAIDs after bariatric surgery.
The next section focuses on bioavailability of metoprolol. In chapter 6 the development of a biorelevant gastrointestinal simulation system (GISS), mimicking conditions before and after Roux-en-Y gastric bypass (RYGB), for in vitro evaluation of the pharmaceutical availability of drugs frequently used by patients after RYGB, is described. Release profiles of metoprolol from metoprolol tartrate immediate release tablets and various metoprolol controlled-release tablets were determined. The objective of chapter 7 was to validate a simple, sensitive LC-MS method to quantify metoprolol and its metabolite α-hydroxymetoprolol in human serum for application
in pharmacokinetic studies. In chapter 8, we performed an explorative, two-phase, single oral dose pharmacokinetic study of metoprolol in female patients 1 month before and 6 months after RYGB. The aim of this study was to assess the effect of RYGB on the bioavailability of metoprolol from immediate and controlled-release tablets. Finally, in chapter 9, we complete this thesis with a general discussion on the clinical impact of our research. The main findings in this thesis will be placed in perspective of future research.
R E F E R E N C E S
1. World Health Organization. Obesity and overweight: fact sheet No. 311. http://www.who.int/ mediacentre/factsheets/fs311/en/. Updated June 2016. Accessed July 5, 2016.
2. RIVM. Feiten en cijfers over volksgezondheid en zorg. https://www.volksgezondheidenzorg. info/onderwerp/overgewicht/cijfers-context/huidige-situatie#node-overgewicht-volwassenen. Accessed October 2, 2016.
3. Aune D, Sen A, Prasad M, et al. BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. BMJ 2016;353:i256.
4. Bray GA, Frühbeck G, Ryan DH, et al. Management of obesity. Lancet 2016;387:1947-56.
5. Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 2016;315:2424-34. 6. Geneesmiddelenbulletin. De medicamenteuze behandeling van overgewicht. Gebu 2015;49:111-8. 7. Colquitt JL, Pickett K, Loveman E, et al. Surgery for weight loss in adults. Cochrane Database Syst Rev.
2014;8:CD003641.
8. Chang SH, Stoll CRT, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. JAMA Surg. 2014;149:275-87. 9. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative, nutritional,
metabolic, and nonsurgical support of the bariatric surgery patient – 2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Rel Dis. 2013;9:159-91.
10. Fried M, Yumuk V, Oppert JM, et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Surg. 2014;24:42-55.
11. Angrisani L, Santonicola A, Iovino P, et al. Bariatric surgery worldwide 2013. Obes Surg. 2015;25:1822-32.
12. Dutch Audit for Treatment of Obesity (DATO) in: Dutch Institute for Clinical Auditing (DICA) Jaarrapportage 2015. p 80. https://www.dica.nl/media/332/DICA-jaarrapportage-2015.pdf.
Accessed Nov 21, 2016.
13. Aarts EO. Results and complications of bariatric surgery. Thesis. Radboud University Nijmegen; Nijmegen, 2014.
14. Leff DR, Heath D. Surgery for obesity in adulthood. BMJ 2009;339:b3402.
15. Spaniolas K, Kasten KR, Brinkley j, et al. The changing bariatric surgery landscape in the USA. Obes Surg. 2015;25:1544-6.
16. Vincent RP, le Roux CW. Changes in gut hormones after bariatric surgery. Clin Endocrinol. 2008;69:173-79.
17. Ionut V, Bergman RN. Mechanisms responsible for excess weight loss after bariatric surgery. J Diabetes Sci Technol 2011;5:1263-82.
18. Hofsø D, Jenssen T, Hager H, et al. Fasting plasma glucose in the screening for type 2 diabetes in morbidly obese subjects. Obes Surg 2010;20:302-7.
19. Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683-93.
20. Dixon JB, le Roux CW, Rubino F, et al. Bariatric surgery for type 2 diabetes. Lancet 2012;379:2300-11. 21. Buchwald H. The evolution of metabolic/bariatric surgery. Obes Surg. 2014;24:1126-35.
22. Berg P, McCallum R. Dumping syndrome: a review of the current concepts of pathophysiology, diagnosis, and treatment. Dig Dis Sci. 2016;61:11-18.
23. Stein J, Stier C, Raab H, et al. Review article: the nutritional and pharmacological consequences of obesity surgery. Aliment Pharmacol Ther. 2014;40:582-609.
24. Douglas IJ, Bhaskaran K, Batterham RL, et al. Bariatric surgery in the United Kingdom: a cohort study of weight loss and clinical outcomes in routine clinical care. PLOS Med. 2015;12:e1001925. doi:10.1371/ journal.pmed. 1001925.
25. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical complications. Obes Rev. 2010;11:41-50.
26. Smith A, Henriksen B, Cohen A. Pharmacokinetic considerations in Roux-en-Y gastric bypass patients. Am J Health Syst Pharm. 2011;68:2241-7.
27. Greenblatt HK, Greenblatt DJ. Altered drug disposition following bariatric surgery: a research challenge. Clin Pharmacokinet. 2015;54:573-9.
SECTION
II
Jan Peter Yska Susanne van der Linde Véronique V. Tapper Jan A. Apers Marloes Emous Erik R. Totté Bob Wilffert Eric N. van Roon
Published in: Obesity Surgery 2013;23:819-25.
2
CHAP TER
INFLUENCE OF BARIATRIC SURGERY ONTHE USE AND PHARMACOKINETICS OF SOME MAJOR DRUG CLASSES
A B S T R A C T
The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives and thyroid drugs. A reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes. Very few studies have been published on the influence of bariatric surgery on the pharmacokinetics of drugs. After bariatric surgery, theoretically, reduced drug absorption may occur. Correct dosing and choosing the right dosage form for drugs used by patients after bariatric surgery are necessary for optimal pharmacotherapy. Therefore, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics of major drugs.
I N T R O D U C T I O N
Worldwide obesity is a growing problem. In 2008 an estimated 205 million men and 297 million women had a body mass index (BMI) of 30 kg/m² or higher [1]. Bariatric surgery is the only treatment for morbid obesity (BMI > 40) that has been shown to produce long term weight loss [2]. Several metabolic surgical techniques are available includ-ing purely restrictive (gastric bandinclud-ing) and restrictive/malabsorptive (gastric bypass) procedures. Of these techniques, the Roux-en-Y gastric bypass is the most commonly performed procedure [3]. Morbid obesity is associated with many comorbidities and reduced life expectancy [2]. Patients undergoing bariatric surgery have excess weight accompanied by multidrug use for multiple medical comorbidities. Bariatric surgery can influence the prevalence and incidence of comorbidities as well as the pharma-cokinetics of drugs. For accomplishing optimal effects in patients, this might lead to changes in pharmacotherapy. After bariatric surgery, the use of a drug may be contin-ued or stopped, and the dosage or dosage form may be changed because of adverse drug events or to achieve an optimal therapeutic effect. Different surgical procedures may each have specific effects on factors influencing absorption, like drug disinte-gration and dissolution, mucosal exposure, and absorption across the intestine, and therefore the pharmacokinetics of a drug may be changed after bariatric surgery [4]. After procedures involving gastric restriction, drug disintegration and dissolution may be altered by changes in gastric mixing, pH, and gastric emptying. This may affect the absorption of oral solid formulations like coated or controlled release preparations [4]. In diversionary and malabsorptive procedures, absorption may be reduced because of slow dissolution properties of the drug. Absorption of lipophilic drugs may be affected by less bile salt solubilization and enterohepatic recirculation [4]. Because bypass pro-cedures reduce functional gastrointestinal length, drug absorption may be reduced; however “intestinal adaptation”, mucosal hypertrophy within the remaining intestine resulting in an increase of absorptive capacity, might counterbalance this [4]. Although bariatric surgery may theoretically have effects on the pharmacokinetics of drugs, sur-prisingly few clinical data are available.
Reviews so far focused on drug distribution in obesity and after bariatric surgery [5,6] and medication and nutrient administration considerations after bariatric surgery [7]. Padwal et al. reviewed the literature by examining the effects of bariatric surgery on drug absorption in relation to type of procedure [4]. However, drugs used for serious obesity-associated conditions, like major depression and cardiovascular and endo-crine diseases in patients undergoing bariatric surgery, have not been the primary focus yet.For optimal drug use in these conditions, a clear understanding of the influ-ence of bariatric surgery on the pharmacokinetics is necessary. Therefore, we studied the available literature on the influence of bariatric surgery on drug use and the phar-macokinetics of some frequently used drugs for depression, and cardiovascular and endocrine diseases.
L I T E R A T U R E R E V I E W
We performed a PubMed literature search. Search terms included bariatric surgery OR malabsorptive surgery OR weight loss surgery OR gastric bypass OR metabolic surgery AND <name of drug class>.The drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives, and thyroid drugs. The search was limited to articles published in English from January 1990 to October 2012 and is considered up-to-date as of October 12, 2012. Related arti-cles were also reviewed in this search. All titles and abstracts were screened for eligibil-ity. Relevant articles were reviewed to obtain information on the influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. In Table 1, an overview of the number of relevant articles from the literature search is shown.
TABLE 1. Results of PubMed literature search.
PE pharmacoepidemiology; PK pharmacokinetics
Antidepressants
Bariatric surgery may have various effects on the use of antidepressants. On the subject of the use of antidepressants, Segal et al. reported a 9 % decrease in the mean number of prescriptions 12 months after bariatric surgery [8].However, in a retrospec-tive study of 439 patients who had undergone Roux-en-Y gastric bypass, Cunning-ham et al. found that 23 % of the patients had an increase in their antidepressant use, 40 % continued to require the same antidepressant, 18% had a change in antidepres-sant medication, and only 16% had a decrease or discontinued their antidepresantidepres-sant [9]. Voelker et al. reported on the potential effects of gastric bypass surgery on the use of antidepressant medications. Tricyclic antidepressants (TCAs) and Selective Serotonin Reuptake Inhibitors (SSRIs) are highly lipophilic antidepressant drugs, well absorbed in the normal gastrointestinal tract. After gastric bypass surgery, the volume of distri-bution might be loer because of less adipose tissue. The concentration of drug-bin- ding α-1-acid glycoprotein (AAG) has been reported to double in obese patients.
Drug class Retrieved records
Relevant articles Total PE PK Other Antidepressants 42 6 2 2 2 Antidiabetics 360 27 12 1 14 Statins 17 6 2 3 1 Antihypertensive agents 41 10 7 2 1 Corticosteroids 40 4 4 Oral contraceptives 9 4 4 Thyroid drugs 6 5 4 1
In weightloss after surgery, serum AAG may decrease, possibly requiring dose adjust-ments for highly bound drugs like TCAs [10].
In an in-vitro dissolution study, Seaman et al. demonstrated that the solubility of oral psychiatric medication preparations including amitriptyline, venlafaxine, and SSRIs like paroxetine, sertraline and citalopram may be altered after gastric bypass, but they did not reveal differences in absorption [11]. Roerig et al. performed a case-controlled pharmacokinetic study comparing the area under the curve (AUC) for a single dose of sertraline 100 mg between five subjects at 9-15 months after Roux-en-Y gastric bypass and five nonsurgical control subjects [12]. They found the AUC0-10,5 and maximal plasma concentration to be significantly smaller in the surgery group. They conclude that the data suggest that the surgical procedure alters either the amount of drug absorbed or the time during which the absorption occurs, or both [12]. According to Hamad et al., patients taking serotonin reuptake inhibitors may have a risk for reduced bioavailability after Roux-en-Y gastric bypass surgery, so they recommend close psychiatric monitoring after surgery [13]. In 12 patients using different serotonin reuptake inhibitors (venlafaxine, citalopram, escitalopram, sertraline, duloxetine) they carried out pharmacokinetic studies 1 month before and 1, 6 and 12 months after Roux-en-Y gastric bypass. In eight patients, AUC values at 1 month after surgery had decreased in comparison to preoperative values. At 6 months after surgery, in six of these patients AUC levels had returned to baseline or greater [13]. Data from literature on the use and pharmacokinetics of antidepressants after bariatric surgery are limited. However, after bariatric surgery, clinicians should closely monitor patients on antidepressant therapy for recurrence of depressive symptoms and for side effects, adjusting dosage or formulation if necessary.
Antidiabetics
In literature, many articles can be found on the topic of bariatric surgery and antidiabetics. Several reviews on different aspects of bariatric surgery and its influence on type 2 diabetes concluded that surgical treatment for obese patients may be considered an additional treatment option for the management of type 2 diabetes, [14-18]. Bariatric surgery results in significant weight loss and in resolution or improvement of type 2 diabetes mellitus, as shown by cessation or reduction of oral antidiabetics and insulin. In a prospective study on the health benefits of gastric bypass surgery after 6 years, Adams et al. showed that 62 % remission of diabetes was maintained at year 6 [19]. However, details of use of antidiabetic medication are not given.
Articles in which attention is being to paid to the use of antidiabetics may be divided into studies on the effect of bariatric surgery on type 2 diabetes (retrospective studies and randomized clinical trials) and studies on the use of antidiabetic medication after bariatric surgery.
Retrospective studies have been carried out on outcome of type 2 diabetes mellitus after bariatric surgery [20-24], but in all of these studies with varying number of pa-tients, different surgical techniques, and sometimes too short follow-up after surgery, the use of antidiabetic medication was not the primary focus.
So far, only three randomized controlled clinical trials have shown superiority of surgery over medical care for type 2 diabetes. In all trials different surgical techniques were used: gastric banding [25], Roux-en-Y gastric bypass and biliopancreatic diver-sion [26], and Roux-en-Y gastric bypass and sleeve gastrectomy [27]. These studies have been carried out on glycemic control parameters after bariatric surgery or on cessation or reduction of medication use for diabetes.
We found relatively few studies on the use of antidiabetic medication after bariatric surgery. They all showed a significant decrease in the use of oral antidiabetics and insulin after surgery [8, 28-31]. However, in these studies, all using different types of bariatric surgery, either the number of included patients using antidiabetics before surgery is small [29,31], or no details were provided on specific oral antidiabetic agents or dosages [8,28,30]. Several studies on the cost of medication in patients after bariatric surgery also showed a significant reduction for diabetes medication [32-38]. So far, only one study on the pharmacokinetics of antidiabetic medication is published. Metformin is the first-line drug of choice for the treatment of type 2 diabetes. Since metformin is primarily absorbed in the upper small intestine, Padwal et al. hypothesized that absorption would be significantly reduced in patients after Roux-en-Y gastric bypass. In a single-dose pharmacokinetic study in 16 non-diabetic patients after gastric bypass and 16 matched control subjects, they studied metformin absorption and bioavailability after administration of two 500 mg tablets. In patients after gastric bypass, they found an increase in metformin absorption and bioavailability in comparison with the control subjects [39]. Further studies are needed to establish whether this finding may have consequences for dosing of metformin after gastric bypass surgery.
Bariatric surgery reduces the use of antidiabetic medication. Studies published so far suffer from methodological problems or do not provide enough details with regard to drug usage. In future studies on the effect of bariatric surgery on type 2 diabetes, specific information should be gathered on the use of antidiabetics (agent, dosage, dosage form). Moreover, more interest is needed for the pharmacokinetics of oral antidiabetics.
Statins
Only a few studies were found on the use of medication after bariatric surgery with data on lipid-lowering agents. Segal et al. investigated the use of medication after bariatric surgery in a cohort study on 6,235 patients. They found that, at 12 months after surgery, the use of medication for dyslipidemia was reduced by 59 % in non-diabetic and by 54 % in diabetic patients, which may suggest a substantial resolution of dyslipidemia [8]. In a study on 298 veterans with hyperlipidemia who had undergone bariatric surgery Maciejewski et al. found that 40 % had discontinued their lipid-lowering medication within 1 year after surgery [30].Schauer et al. showed that there was a significant reduction in the number of medications needed to treat hyperlipidemia in patients after gastric bypass and sleeve gastrectomy as compared with patients on intensive medical therapy for diabetes [27].
Limited data are available on the effects of bariatric surgery on the pharmacokinetics of statins. In two different studies, Skottheim et al. found atorvastatin to be a suitable model drug for investigating the influence of the proximal intestine on drug availability. Atorvastatin shows low bioavailability when orally administered, is highly protein bound, and is a substrate for CYP3A4 and CYP3A5, as well as for the efflux transporter P-glycoprotein. In a study in 12 patients, they investigated the effect of gastric bypass on the bioavailability of atorvastatin. Gastric bypass surgery showed a variable effect on systemic exposure to atorvastatin, ranging from a 2.9-fold decrease to a 2.3-fold increase. The effect is complex but likely to depend on both available absorption area and the metabolic capacity of the bypassed small intestine [40]. In another pharmacokinetic study in ten patients after biliopancreatic diversion with duodenal switch, Skottheim et al. found increased bioavailability of atorvastatin, indicating the great influence of the bypassed highly metabolically active proximal small intestine on bioavailability [41].
Simvastatin, like atorvastatin, is a lipophilic drug; however, it is a prodrug needing hydrolysis for forming the active metabolite [42]. The influence of bariatric surgery on the first-pass metabolism of simvastatin is unknown. Pravastatin is a statin with hydrophilic properties, moderately bound to plasma proteins and not undergoing substantial metabolism by the CYP450 system [42]. Because of these properties, it may be postulated that bariatric surgery hardly affects the pharmacokinetics of this drug. Research is needed to establish whether pravastatin from a pharmacokinetic point of view may be the most appropriate statin after bariatric surgery. Bariatric surgery is effective for decreasing the use of medication for dyslipidemia. The effect of bariatric surgery on the pharmacokinetics of statins is complex; therefore, after surgery, patients on statins should be retitrated on the lowest dose possible while monitoring the plasma lipid profile.
Antihypertensive agents
In three different studies on the costs of medication in obese individuals undergoing bariatric surgery, significant savings for cardiovascular or hypertensive medication were shown, implying decrease in use of medication [32,33,37].
In a study on 42 patients with excess weight following Roux-en-Y gastric bypass surgery Donadelli et al. found that all indicators of cardiac risk improved significantly after gastric bypass, except for systolic and diastolic blood pressure, with 43 % of the patients taking antihypertensive medication before surgery and 17 % continuing antihypertensive treatment 2 years after surgery [43]. In a study on medication use after bariatric surgery, the use of cardiac medication decreased by 54 % and the use of diuretics decreased by 51 % in the postoperative period [44]. Segal et al. reported a 51 % decline in the use of medication for hypertension at 12 months after bariatric surgery [8]. In their study on bariatric surgery versus intensive medical therapy in obese patients with diabetes, Schauer et al. also showed that there was a significant reduction in the use of antihypertensive agents in patients after gastric bypass and sleeve gastrectomy as compared with patients on intensive medical therapy for diabetes [27]. In a study on the impact of bariatric surgery on comorbidities and medication use, a significant decrease for total cardiovascular disorders from 43.6 % before the operation to 14.2 % after 3 years was observed. The use of cardiovascular medication dropped from 43.7 % presurgery to 25.5 % 3 years postsurgery [45]. For antihypertensive treatment diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers are frequently used. In literature, only studies on pharmacokinetics of beta blockers were found.
Wójcicki et al. investigated the pharmacokinetics of propranolol and atenolol in patients after partial gastric resection [46]. The study was carried out in 29 patients after gastric resection with Billroth I anastomosis and in 18 healthy volunteers as controls. Pharmacokinetics of propranolol and atenolol was studied after a single oral dose of 80 mg and 100 mg, respectively. The pharmacokinetic parameters of propranolol after partial gastrectomy were significantly different from those in the control subjects: a decrease in AUC by 32 % and a decrease in Cmax by 20 % were noted. However, the pharmacokinetic parameters of atenolol in patients after partial gastrectomy did not reveal any significant differences compared with the controls [46]. Although propranolol and atenolol are both basic agents, they have different solubilities as propranolol is a lipophilic drug and atenolol is a hydrophilic compound. Following partial gastrectomy, the most important parameter alterations are decreased acidity and gastric secretion, and accelerated motility. An increase in pH of gastric secretion promotes the absorption of weakly basic drugs, including propranolol and atenolol [47]. However, an increase of pH will decrease the solubility of basic drugs in the stomach, contributing to a reduction in the rate of absorption in the small intestine. The lipophilicity of propranolol may be responsible for the observed impairment of drug absorption in patients after partial gastrectomy.
After bariatric surgery, the use of antihypertensive agents is reduced. If beta blocker therapy after bariatric surgery is still necessary, a hydrophilic compound like atenolol may be preferred.
Corticosteroids
Several studies were performed to investigate the effects of bariatric surgery on the use of respiratory medication and oral and inhaled corticosteroids. All of these studies showed a decrease in the use of antiasthmatic drugs [44,45,48,49]. In patients treated with laparoscopic adjustable banding, which is associated with less weight loss, reduc-tion in the use of medicareduc-tion was less.
Research on the use of oral corticosteroids after bariatric surgery is limited. There are no studies on the absorption or pharmacokinetics of corticosteroids after bariatric surgery.
Oral contraceptives
Merhi provided an overview of reproductive physiology after bariatric surgery [50]. He concluded that bariatric surgery seems to improve fertility status, sexuality, pregnancy outcomes, and reproductive hormone profile, but bariatric surgery is possibly linked to contraceptive failure with the use of oral contraceptives. The use of oral contracep-tives might not be trusted, most likely because of malabsorption entailed by bypass-ing part of the gastrointestinal system and postoperative complications like diarrhea and vomiting [50]. In a prospective study in 40 women who underwent biliopancreatic diversion (BPD), Gerrits et al. evaluated the hormone status preoperatively and post-operatively. Fertility increased after BPD. From the nine patients using oral contracep-tives, two patients developed an unforeseen pregnancy in the postoperative period despite the use of the same oral contraceptive before and after BPD [51]. According to Merhi, the effect of oral contraceptives after weight loss by malabsorptive bariatric surgery is understudied. Prescribing oral contraceptives needs to be done with cau-tion. To minimize the side effects of oral contraceptives increasingly lower hormone dosages are used. Attention is needed for the postoperative period of surgical weight loss that may further reduce the bioavailability of oral contraceptives and thus com-promise contraceptive protection. Other methods of contraception might be safer [52]. In a systematic review of the literature, Paulen et al. also concluded that evidence regarding the effectiveness of oral contraceptives in women with a history of bariatric surgery is quite limited [53].
In literature, data on the safe and effective use of oral contraceptives after bariatric sur-gery are very limited. Clinicians should be aware of possible drawbacks of using oral contraceptives. Alternative methods of contraception might be considered.
Thyroid drugs
In a cohort study on 6,235 patients with bariatric surgery, Segal et al.found that the probability of thyroid replacement medication use per person at surgery was 0.17. With regard to medication use, they showed that in a time period from before bariatric surgery up to 12 months afterwards the medication use per person for thyroid replacement medication remained relatively constant [8]. Different results for the use of thyroxine medication after bariatric surgery were found in two studies with a small number of patients. In a retrospective study of patients who underwent laparoscopic Roux-en-Y gastric bypass, 23 of 224 (10.3 %) patients were treated for hypothyroidism pre-operatively. After surgery, hypothyroidism improved and thyroxine requirements were reduced in ten of 23 (43.5 %) patients [54]. In a retrospective review of 20 morbidly female patients with hypothyroidism who underwent laparoscopic Roux-en-Y gastric bypass surgery, Fazylov et al. found that based on the use of thyroid medication hypothyroidism improved or remained unchanged in most patients except for those whose thyroid disease was autoimmune in nature [55].However, Gniuli et al. studied thyroid function in 45 patients before and after biliopancreatic diversion and concluded that the surgery increased the prevalence of subclinical or even frank hypothyroidism. Before surgery, 23 % of the subjects had subclinical hypothyroidism; at 2 years after surgery, 40.4 % of the study population had subclinical hypothyroidism. After surgery, TSH levels were increased, while free triiodothyroxine (fT3) and iodine excretion with urine decreased significantly. Levothyroxine supplementation was increased in all previous subclinical hypothyroid subjects and was started in newly onset subjects. Low circulating levels of fT3 may be a consequence of inadequate levothyroxine replacement due to altered gut absorption. However, fT3 decrease could also be caused by the surgically induced anatomical modifications of the gastrointestinal tract interfering with the enterohepatic axis. Free T3 is mainly produced in the liver by T4 de-iodination, excreted with the bile, and reabsorbed through the enterohepatic circulation. After biliopancreatic diversion, the enterohepatic circulation is an open loop, resulting in fecal loss of fT3 [56].
Rubio et al. showed that levothyroxine absorption was not decreased after Roux-en-Y gastric bypass surgery [57]. They conducted a pharmacokinetic study in two groups of 15 patients each, just before or 2-3 months after surgery, administering a single oral dose of 600 µg of levothyroxine. The subjects did not act as their own control. They found that increases in total T4 and free T4 were higher in the surgical group in comparison to the non-surgical group. However, there was a significant delay in the absorption of levothyroxine in patients who had undergone surgery [57].
Obese patients scheduled for bariatric surgery should be screened for thyroid dysfunction and, if replacement therapy is necessary, strictly monitored.
C O N C L U S I O N
The number of patients undergoing bariatric surgery is rapidly increasing. Some studies on medication use before and after bariatric surgery showing a reduction in medication use for comorbidities like diabetes, hypertension, and hyperlipidemia have been published [8, 44,45], but studies assessing the change in the use of medication before and after bariatric surgery did not consider changes in dosage or dosage form, which might have been implemented because of adverse drug events or an inadequate therapeutic effect.
Literature on the influence of bariatric surgery on the pharmacokinetics of frequently used drugs is sparse. Theoretically, reduced drug absorption may occur after bariatric surgery. Medication formulations may then be critical to ensure adequate absorption [58].
At least for drugs and drug classes frequently used by patients after bariatric surgery, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics. Clinical drug intervention studies may be performed next. Until more is known about the optimal use of drugs (dosage and dosage form) after bariatric surgery, close monitoring of the use of medication and its effects in the individual patient is necessary.
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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
CHAP TER
INFLUENCE OF
BARIATRIC SURGERY ON THE USE OF MEDICATION
A B S T R A C T
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.
I N T R O D U C T I O N
Obesity has become a major global health problem. Managing obesity by diet, physical exercise, or behavioral therapies has very limited success in achieving long-term 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.
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.
M E T H O D S
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 2011. 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
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 two-sided 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.
R E S U LT S
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 pre-surgery to 31.3±5.6 kg/m² 12 months after pre-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 restrictive-malabsorptive 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 A10 71.3 % (95 % CI 57.2 to 85.4)), drugs acting on the cardiovascular system (ATC-class C 34.5 % (95 % CI
28.2 to 43.0)), drugs acting on the musculoskeletal system (ATC-class M 33.2 % (95 % CI - 1.9 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 + 91.9 % (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 0.40 1 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.
