|Year : 2023 | Volume
| Issue : 1 | Page : 13-19
Combining metabolic surgery with medications for type 2 diabetes: Is there a benefit?
Alexis Sudlow1, Dimitri J Pournaras2, Carel W le Roux3
1 Department of Bariatric Surgery, Southmead Hospital, Bristol, UK; Department of Experimental Pathology, University College Dublin, Dublin, Ireland
2 Department of Bariatric Surgery, Southmead Hospital, Bristol, UK
3 Department of Experimental Pathology, University College Dublin, Dublin, Ireland
|Date of Submission||22-Sep-2022|
|Date of Acceptance||27-Sep-2022|
|Date of Web Publication||06-Dec-2022|
Dr. Carel W le Roux
Department of Experimental Pathology, University College Dublin, Dublin
Source of Support: None, Conflict of Interest: None
Bariatric surgery has been consistently demonstrated in randomized controlled trials to be the most effective treatment currently available for patients with Type 2 diabetes mellitus (T2DM) and obesity. In spite of this, with the emergence of longer-term data, it is now becoming apparent that some of the metabolic benefits afforded by bariatric surgery fatigue with time, prompting clinicians to re-consider how patients should be managed in the postoperative period. As is seen with many other chronic diseases including peripheral vascular disease as well as some cancers, surgery is seen as a means of inducing disease control with medications being employed to maintain sustained remission. In recent years, there have been remarkable advances in pharmacotherapy for the treatment of T2DM as well as additional agents which can produce clinically significant weight loss. Having recognized the potential need for further treatment following bariatric surgery along with the availability of highly effective medical therapies presents the opportunity to explore a multimodal approach to care, combining medications with surgery to potentially improve long-term outcomes.
Keywords: Multimodal care, obesity, pharmacotherapy, Type 2 diabetes mellitus
|How to cite this article:|
Sudlow A, Pournaras DJ, Roux CW. Combining metabolic surgery with medications for type 2 diabetes: Is there a benefit?. J Bariatr Surg 2023;2:13-9
|How to cite this URL:|
Sudlow A, Pournaras DJ, Roux CW. Combining metabolic surgery with medications for type 2 diabetes: Is there a benefit?. J Bariatr Surg [serial online] 2023 [cited 2023 Mar 22];2:13-9. Available from: http://www.jbsonline.org/text.asp?2023/2/1/13/362872
| Introduction|| |
Although initially conceived as a treatment with the primary goal of weight reduction, following bariatric surgery, it became apparent that it could produce not only weight loss but improvements in metabolic disease associated with obesity, resulting in the development of the term, “metabolic surgery.” Some of the earliest bariatric operations involving jejunoileal bypass gave the first indication that these procedures could improve glycemic control in patients with diabetes while also treating associated cardiovascular risk factors such as hyperlipidemia., Data emerging from an observational study in 1992 of nearly 500 patients undergoing roux en Y gastric bypass (RYGB) raised interest in the concept of employing a surgical procedure to treat Type 2 diabetes mellitus (T2DM), a disease which had always been seen as a purely medical problem. Given the established link between obesity and the development of T2DM, many of the benefits of bariatric surgery on improving glycemic control at the time were initially attributed to weight loss alone. Subsequent mechanistic studies, however, demonstrated that powerful neurohormonal changes occurring in a weight loss-independent manner contribute to a rapid normalization in glycemia within days of surgery.
Early treatment strategies in the treatment of T2DM largely focused on glycemic targets; however, the landmark STENO-2 trial which demonstrated a reduction in all-cause mortality as well as cardiovascular mortality associated with goal-directed medical therapy aimed at controlling glycemia, blood pressure, and lipids now forms the basis of most treatment algorithms. Reflecting these findings, the American Diabetes Association (ADA) Standards of Medical Care in Diabetes focuses on these treatment targets; however, achieving adequate control using medications alone remains challenging, with studies suggesting that <20% of patients with T2DM reach all the three therapeutic goals. In recognition of the challenges of adequately treating T2DM in patients with medication and/or lifestyle intervention, the Second Diabetes Surgery Summit-II developed guidelines which included bariatric surgery as the central component in the management strategy. These guidelines have since been endorsed by both the ADA and International Diabetes Federation (IDF), with bariatric surgery becoming a central element in addition to medications for patients with T2DM and obesity., There is now evidence from more than 13 randomized controlled trials (RCTs) which demonstrate the beneficial effects of bariatric surgery on glycemic control compared to medications alone, irrespective of the procedure performed. It is, however, worth noting that there is variability between procedures with regard to the anticipated improvements in metabolic disease.
Many early studies demonstrated not only an improvement in glycemia but also presented the suggestion that patients could actually be cured surgically with bariatric surgery, producing sustained diabetes remission. Longer-term evidence has since demonstrated that although a subgroup of patients will go in to remission, irrespective of weight regain, a substantial proportion will experience a relapse of diabetes according to the ADA criteria. It should be recognized that in this population who have experienced a relapse of T2DM, glycemic control remains good. In light of the high likelihood of relapse, the perception of bariatric surgery as a long-term cure for T2DM has been replaced with a more pragmatic view of surgery as a means of inducing remission with a resultant long-term improvement in glycemic control, cardiovascular risk, and mortality. Having recognized the fact that the metabolic effects of bariatric surgery appear to become attenuated with time calls in to question the current approach to long-term management for patients with T2DM following bariatric surgery in which all medications normally used are stopped. At present, there is no Level 1 evidence to guide how these patients should be treated; however, the rates of relapse would suggest that there may be a role for combining medications for T2DM with surgery to improve outcomes, an approach which is currently being investigated.
| Understanding the Need for Adjuvant Treatment|| |
Although bariatric surgery has been consistently demonstrated in RCTs to be superior to medical treatment with regard to both weight loss and control of T2DM, the concept of adopting a multimodal approach to care, combining medication with surgery, increasingly warrants investigation given the high likelihood of T2DM relapse following a period of remission. The longest follow-up data from an RCT comparing medication to surgery which included biliopancreatic diversion (BPD) and RYGB found that nearly 60% of patients who were in remission at 2 years had experienced a relapse of T2DM by 10 years. Looking at the two groups individually, the relapse rates were 66% among those who had RYGB and 52% in those who had BPD despite profound long-term metabolic changes. The recent 10-year observational follow-up data from the SLEEVEPASS RCT found similarly with T2DM remission rates after sleeve gastrectomy (SG) and RYGB of 26% and 33%, respectively. RCTs with shorter-term follow-up such as the STAMPEDE which compared bariatric surgery in the form of RYGB or SG to medical therapy found that at 5 years only 29% of those undergoing RYGB and 23% undergoing SG met the ADA criteria for remission. Although this is arguably a high rate of relapse, these procedures remain effective in the long term as a treatment of T2DM in patients with obesity as judged by the much improved glycemic control. As is seen with other chronic conditions, not only are lifelong treatment strategies needed but also disease processes inevitably progress. There is thus a need for treatment intensification which in this context should include consideration of additional pharmacotherapy as an adjuvant treatment to surgery to maintain or improve disease control.
| Investigating Combinational Care|| |
Combinational therapy has become the cornerstone in the management of T2DM with patients typically being treated with multiple pharmacological agents; however, the possibility of extending this concept to include surgery has not been widely investigated or applied. Studies examining the treatment of T2DM in patients with obesity have typically adopted a comparative approach, looking at either medications or surgery; however, there is a growing need to consider what can be achieved in adopting a combinational approach, combining the two modalities. The high rate of T2DM relapse in the long term has clearly demonstrated the need. Looking to other fields such as the treatment of cancer whereby surgery is a means of inducing disease remission and medications are used to sustain control in the long term has also demonstrated the potential for adopting a similar approach in this context.
At present, there is limited data from RCTs which have investigated the potential for combining bariatric surgery with medications. However, this is increasingly being recognized as a potential therapeutic target, particularly given the recent developments in pharmacotherapy for both weight loss and the treatment of T2DM. One such study which has investigated the role of multimodal care is the STAMPEDE study in which intensive medical therapy alone (targeting both weight loss and glycemic control with biguanides, thiazolidinediones, sulfonylureas, pramlintide, insulin, and glucose-like peptide-1 (GLP-1) analogs as well as ADA criteria for lipids and hypertension [HTN]) was compared to surgery (RYGB or SG) plus intensive medical therapy. Over a 5-year follow-up period, they found that 38% of patients in the RYGB and 24% in the SG achieved T2DM remission compared to 5% in the intensive medical therapy group. Further supporting the concept of combining medications with surgery, the MOMS study was an RCT comparing best medical therapy (BMT) to RYGB in patients with T2DM and established microalbuminuria to examine remission of albuminuria. Medications with recognized benefits for macro and microvascular complications including, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins as well as glucose-lowering drugs and metformin were continued in both the BMT and RYGB groups. At 24 months, the albuminuria remission rate in the BMT group was 55% versus 82% in the RYGB group, demonstrating not only the safety of combining medication with surgery but also its efficacy compared to medical therapy alone.
| Developments in Pharmacotherapy|| |
Although there has been increasing recognition of the need for adjuvant therapy for patients with T2DM and obesity undergoing surgery to enhance or prolong its metabolic effects, many previous studies have focused on the development of novel surgical procedures, the modification of existing ones as well as considering the role of revisional surgery. This focus in part reflected a lack of effective pharmacological options; however in recent years, there has been a rapid expansion in the number of safe and effective medications which could be considered potential adjuvant therapies to complement or enhance the effects of bariatric surgery either through weight loss alone or as diabetes medications, improving glycemic control while also enhancing weight loss. Although the majority of studies at present investigating the safety and efficacy of these medications is largely restricted to standalone medical therapy for T2DM and obesity, the promising results have raised questions as to what could be achieved if combined with surgery and warrants further investigation.
| Glucose-Like Peptide-1 Analogs|| |
There are a number of GLP-1 analogs which are currently licensed for use in the treatment of T2DM as glucose-lowering agents, but studies have also demonstrated their efficacy in inducing clinically significant weight loss and may be safely used for that indication alone. GLP-1 analogs act in a glucose-dependent manner to stimulate insulin secretion while also inhibiting glucagon production and increasing insulin sensitivity in peripheral tissues. In addition to their effects in the regulation of glycemia, GLP-1 analogs promote weight loss by slowing the rate of gastric emptying as well as by acting centrally within the nucleus tractus solitaritus to promote satiety.
| Liraglutide|| |
Liraglutide is a GLP-1 analog which is administered as a once-daily subcutaneous injection with the dose titrated to a maximum of 3 mg daily. In the SCALE Diabetes trial which was a placebo controlled parallel-group trial involving nearly 850 participants with obesity and T2DM, weight loss of >10% was seen in 25% of those treated with maximum dose liraglutide after 56 weeks compared to 6.9% with placebo. Similarly, the SCALE Insulin RCT demonstrated in patients with insulin-dependent T2DM and obesity that over the 56-week study, treatment with liraglutide and intensive behavioral therapy resulted in >5% weight loss in more than 50% of patients compared to 24% placebo. In addition to weight loss, there were more hypoglycemic events recorded with placebo while liraglutide reduced glycated hemoglobin (HbA1c) by −1.1% versus −0.6% in the control arm. One of the few available RCTs investigating the use of adjuvant pharmacotherapy following bariatric surgery is the GRAVITAS study. In the 26-week trial, patients with an HbA1c >48 mmol/mol (>6.5%) at least 1 year following surgery were given either 1.8 mg of liraglutide or placebo. At the conclusion of the trial, patients in the liraglutide group were found to have a reduction of 13.3 mmol/mol in HbA1c and a mean weight loss of −4.23 kg in weight compared to placebo. These findings are in keeping with a retrospective analysis of 117 patients post bariatric surgery who experienced weight regain. Following a mean treatment period of 7.6 months, patients lost −0.6.3 kg on 3.0 mg of liraglutide with the weight loss remaining statistically significant after 1 year.
| Semaglutide|| |
Acting by a similar mechanism of action, semaglutide is a GLP-1 analog that is available as a once-weekly subcutaneous injection or oral table taken once daily. Looking at the safety and efficacy of once-weekly subcutaneous semaglutide, the SUSTAIN-1 trial demonstrated a 1.6% decrease in HbA1c with 1 mg semaglutide at 30 weeks compared to 0.02% with placebo. In addition to improved glycemic control, there was a 4.5 kg decrease in body weight in the semaglutide group versus 0.98 kg in the placebo group (Sorli). The subsequent SUSTAIN-6 trial demonstrated the cardiovascular benefits in patients with T2DM, showing a significantly reduced risk of death from cardiovascular causes as well as nonfatal myocardial infarction (MI) and stroke in patients taking once-weekly subcutaneous semaglutide (0.5–1 mg) compared to placebo. The subsequent SUSTAIN-FORTE study investigated the efficacy and safety of higher dose once-weekly subcutaneous semaglutide (2 mg) in patients with inadequately controlled T2DM, showing even greater reductions in HbA1c and body weight compared to lower dose (1 mg), establishing high-dose semaglutide as an option for those in need of treatment intensification (Frias, 2021). The PIONEER-1 study examining the efficacy of oral semaglutide versus placebo demonstrated a statistically significant difference in HbA1c at all doses given in the trial (3, 7, and 14 mg) compared to placebo as well as a significant reduction in body weight at the 14 mg dose. The subsequent PIONEER-6 study examined the cardiovascular safety of oral semaglutide in patients with T2DM versus placebo. The trial demonstrated noninferiority with the primary endpoint occurring in 3.8% of the patients in the semaglutide group compared to 4.6% in the placebo group. There is limited evidence looking at the use of semaglutide in the postoperative period; however, a retrospective analysis of 44 patients without T2DM with insufficient primary weight loss or weight regain demonstrated a total weight loss of -10.3% after 6 months of treatment with semaglutide. It is worth noting that the dose used in this trial was 0.5 mg s/c once weekly which is substantially lower than the 1–2 mg doses investigated trials with semaglutide as monotherapy.
| Sodium-Glucose Transport-2 Inhibitors|| |
Although these medications are primarily used for the treatment of diabetes as they improve glycaemic control, patients also lose weight and fewer cardiovascular events. Sodium-glucose transport-2 inhibitors act by inhibiting glucose reuptake in the proximal convoluted tubule of the kidney which is responsible for nearly 90% of filtered glucose reabsorption, promoting glycosuria and reducing plasma glucose levels.
| Canagliflozin|| |
A double-blind placebo-controlled RCT of nearly 600 patients demonstrated the efficacy of canagliflozin in improving glycemic control as well as improving weight loss and blood pressure. At the end of the 26-week study, those in the 300 mg canagliflozin group had a reduction in HbA1c of -1.0% compared to 0.1% in the placebo arm. A subsequent 26-week extension of the primary study found a -4.4% reduction in body weight in the canagliflozin arm. Looking specifically at the effect of canagliflozin on cardiovascular and renal events, the CANVAS RCT included nearly 10,000 patients with T2DM and high cardiovascular risk. In this placebo-controlled trial with a mean follow-up of 188 weeks, there was fewer death from cardiovascular causes, nonfatal MI, or stroke in the canagliflozin group, occurring in 26.9 participants versus 31.5/1000 patient years. The overall renal outcomes were not different aside from a potential benefit with regard to the progression of albuminuria. The subsequent CREDENCE placebo-controlled RCT examined the effect of canagliflozin on patients with T2DM and established albuminuria chronic kidney disease. After a median follow-up of 2.6 years, the study demonstrated the relative risk of the primary outcome which was a composite of end-stage renal failure, a doubling of the serum creatinine level or death from renal or cardiovascular causes was 30% lower in the canagliflozin group as well as a lower risk of cardiovascular death, MI, or stroke. The effects of canagliflozin in patients who experienced a relapse of T2DM after a period of remission following bariatric surgery was investigated in a small, randomized prospective study of 16 patients. After a treatment period of 6 months, there was a 1.24 kg/m2 reduction in body mass index (BMI) and 3.7 kg reduction in body weight with canagliflozin compared to placebo.
| Empagliflozin|| |
The EMPA-REG MET trial was a placebo-controlled trial examining the effects of 10 or 25 mg of empagliflozin compared to placebo on HbA1c in patients with T2DM already taking metformin. At the trial conclusion at 24 weeks, there was a -0.8% reduction in HbA1c with 25 mg compared to -0.1% in patients taking placebo. A 56-week extension trial found sustained reductions in HbA1c with empagliflozin as well as an adjusted mean change from baseline weight of -2.2 kg for empagliflozin 25 mg compared to placebo. The effects of empagliflozin on cardiovascular morbidity and mortality were investigated in the EMPA-REG OUTCOME study which was a placebo-controlled RCT. The study included more than 7000 patients with T2DM at high cardiovascular risk with a median observation time of 3.1 years and found the primary composite endpoint of death from cardiovascular causes, nonfatal MI, or stroke occurred in 10.5% in the empagliflozin group compared to 12.1% in the placebo group. They also found a 38% relative risk reduction in death from cardiovascular causes, a 35% relative risk reduction in hospitalization from heart failure, and a 32% relative risk reduction in death from any cause in the placebo group compared to placebo.
| Combinational Agents|| |
Dual glucose-dependent insulinotropic polypeptide/glucose-like peptide-1 agonists
Tirzepatide is one of the newest medications available and is a combinational agent, mediating its effects by acting as a glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist. Similar to semaglutide, tirzepatide is given via a once-weekly subcutaneous injection. In the SURPASS-2 trial, nearly 2000 patients with obesity and T2DM already taking metformin were randomized 1:1:1:1: to receive either 5, 10, or 15 mg of tirzapetide or 1 mg of semaglutide. At the end of the 40-week follow-up period, all doses of tirzepatide were non inferior to semaglutide and there was a maximum reduction of -2.3 percentage points in HbA1c in the group randomized to 15 mg tirzapetide compared to -1.86 in the semaglutide group. Although not including patients with T2DM, the SURMOUNT-1 trial demonstrated 20% weight loss in nearly 60% of patients on the maximum dose of tirzapetide and holds promise as a treatment which will also be effective in inducing weight loss in patients with diabetes in future trials. The most common side effects of tirzapetide were shown to be gastrointestinal including nausea, diarrhea, and vomiting and resulted in treatment discontinuation in 6.2% of patients at the highest dose.
Amylin analog/glucose-like peptide-1 analog
Cagrisema which is a combinational agent comprised of the amylin analog, cagrilintide, and the GLP-1 analog, semaglutide has recently completed Phase 2 trials involving 92 patients. The trial investigated the safety and efficacy of the once-weekly subcutaneous injection (2.4 mg cagrilintide +2.4 mg semaglutide) compared to the individual components given separately in patients with T2DM. Over a treatment period of 32 weeks, those treated with cagrisema had a reduction in HbA1c of 2.2% compared to 1.8% with semaglutide and 0.9% with cagrilintide. There was also an impressive reduction in weight with those in the cagrisema group reaching a 15.6% weight loss compared to 5.1% with semaglutide and 8.1% with cagrilintide. Further Phase 3 studies are awaited.
| Antiobesity Medications|| |
In recent decades, the primary focus of treatment for patients with obesity and T2DM has been on improving indices of glycemia while modifying cardiovascular risk factors; however, there has been increasing recognition of the importance of targeting weight in itself. T2DM and obesity are inherently linked, heterogeneous diseases, thus achieving the primary goal of weight reduction is being recognized as a means of modifying the underlying disease process which drives the development of metabolic complications. Most studies would support that sustained weight loss of 15% is required in order to have a substantial impact on improving glycemic control or inducing T2DM. Although this degree of weight loss is not achievable with any currently available anti-obesity medications (AOMs), it may be that for patients with suboptimal weight loss or weight regain, they may reach this threshold by combining medications with surgery. Orlistat is one of the most widely prescribed AOMs; however, studies would suggest that it produces only modest reductions in weight with mean placebo-subtracted weight loss of approximately 2.5%. Several newer agents which act centrally to modify appetite and satiety are now widely available including, phentermine-topiramate and naltrexone-bupropion. Although there are no large-scale studies looking at their efficacy in combination with bariatric surgery, studies would suggest as standalone therapy, they produce a mean placebo-subtracted weight loss of 3%–7% in patients with T2DM. A small prospective study examining the effect of combining phentermine/topiramate in patients with a BMI >50 kg/m2 undergoing/SG found a statistically significant reduction in BMI in those taking phentermine/topiramate in conjunction with SG compared to those undergoing SG alone. At 24 months postop, patients taking phentermine/topiramate had a mean BMI of 33.8 kg/m2 compared to 42 kg/m2 with an 11.2% greater weight loss compared to SG alone. A retrospective review of 13 patients who experienced weight loss plateau or weight regain following either RYGB of adjustable gastric banding found that after a treatment period of 90 days, patients lost a mean of 3.81 kg or 12.5% excess weight loss (EWL). Although both of these studies are small nonrandomized, it supports the concept that surgery and AOMs can be safely combined to produce additional weight loss in the postoperative period.
| Combining Medication with Surgery|| |
Although there have been remarkable advances in the treatment of T2DM and obesity with regard to surgical and medical treatment, these have largely occurred in parallel, with little overlap between the two modalities. The STENO-2 trial marked a turning point in the medical management of T2DM, having demonstrated the importance of moving away from a purely glucocentric model of care to adopting goal-directed medical therapy. In employing an intensive, multifactorial treatment strategy to target modifiable cardiovascular risk factors using combinational pharmacological care, the study demonstrated a reduction in death from all causes as well as due to cardiovascular events. The 21-year follow-up data demonstrated a median survival benefit of 7.9 years in the intensive medical therapy group compared to conventional medical care. In keeping with what was seen in the UKPDS trial where even a short period of improved glycemic control improved long-term mortality, a similar legacy effect was seen with a sustained reduction in mortality in the original goal-directed medical therapy group compared to control despite similar interventions in both groups over the majority of the follow-up period. There appeared to be a plateau with regard to the benefits of intensive medical therapy with a similar mortality benefit between the two groups between the 13.3-year and 21-year analysis. This observation is in keeping with the model of caring for chronic diseases whereby treatment intensification is often required in order to maintain long-term control. The results of this study prompted a critical shift in the management of T2DM and came to shape the treatment algorithms that have been endorsed by governing bodies worldwide but critically also highlighted the need for employ multimodal interventions in order to improve outcomes. Although the multimodal treatment in this study consisted of medications acting on multiple distinct targets, it illustrated proof of concept in that combinational care is not only safe but effective.
In spite of remarkable improvements in morbidity and mortality achieved through intensive multimodal medical care, the concept of adopting a surgical approach which could not only help treat diabetes but actually induce remission began to emerge and gain popularity. Early evidence from clinical trials demonstrated that in addition to producing clinically significant weight loss which was sustained in the long term, bariatric surgery resulted in powerful neurohormonal changes which produced a rapid normalization of glycemia within days of surgery, independent of weight loss. In recognition of these weight loss dependent and independent improvements in glycemia as well as offering the possibility of producing remission of diabetes, bariatric surgery became a central element in the treatment algorithm for patients with obesity and T2DM for both the ADA and IDF., In spite of the initial promise of a potential cure for T2DM, the emergence of longer-term data provided a more realistic view of bariatric surgery as a means of inducing diabetes remission with a substantial proportion of patients experiencing a relapse in spite of sustained improvements in glycaemia. Data from the RCT with the longest follow-up period would suggest that at 10 years, only 25% of patients undergoing RYGB maintained diabetes remission and 66% of those who were in remission at 2 years, experienced a relapse although glycemic control remained good.
Although all RCTs to date comparing medication to bariatric surgery for the treatment of obesity and T2DM have shown surgery to be more effective, the recognized diminution of its efficacy over time calls in to question the current approach to managing patients in the long term by employing one single therapeutic modality. Looking to other specialties such as vascular surgery or some cancers, surgery is rarely seen as a standalone treatment rather it is a means of achieving disease control with further medication to sustain remission in the long term. Moreover, in the management of the majority of chronic diseases, including T2DM, treatment with a single medication is rare, rather combinational therapy using agents with synergistic or complementary mechanisms of action has been seen to be more effective. Having recognized both the benefits and limitations of medical or surgical care as a standalone intervention should prompt clinicians to re-consider the concepts illustrated by the STENO-2 trial of employing combinational care, in this case medication and surgery. It is also critical as clinicians to understand the patient perspective on diabetes remission and relapse and consider that studies have shown for many patients, this is the primary reason for undergoing surgery. Limited evidence from trials combining medications with surgery have thus far supported that it is safe and effective although further studies are needed, including many of the recently developed medications. Although some have suggested that these medications may replace surgery perhaps a more realistic and beneficial approach would be to move beyond direct comparisons with a focus on what can be achieved through a combinational approach to care.
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Conflicts of interest
There are no conflicts of interest.
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