- Email: [email protected]
Diabetes management before, during, and after bariatric and metabolic surgery
Accepted Manuscript Diabetes management before, during, and after bariatric and metabolic surgery
Karim G. Kheniser, Sangeeta R. Kashyap PII: DOI: Reference:
S1056-8727(18)30552-X doi:10.1016/j.jdiacomp.2018.06.006 JDC 7226
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
16 May 2018 6 June 2018 7 June 2018
Please cite this article as: Karim G. Kheniser, Sangeeta R. Kashyap , Diabetes management before, during, and after bariatric and metabolic surgery. Jdc (2018), doi:10.1016/ j.jdiacomp.2018.06.006
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ACCEPTED MANUSCRIPT Diabetes management before, during, and after bariatric and metabolic surgery Karim G. Khenisera and Sangeeta R. Kashyapa Department of Endocrinology and Metabolism, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, U.S.a
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Email: [email protected]
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[email protected]
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Address correspondence to: Sangeeta R. Kashyap MD Professor of Medicine 9500 Euclid Ave. (F-20) Cleveland, OH, 44195 Phone: 216-445-2679 Email: [email protected] Fax: 216-445-1656
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ACCEPTED MANUSCRIPT Abstract Metabolic surgery is unrivaled by other therapeutic modalities due to its ability to foster diabetes remission. Metabolic surgery is an integral therapeutic modality in the obese and morbidly obese populations because pharmacological and behavioral therapy often fail to effectively manage
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type II diabetes over the long run. However, given the relative invasiveness of the metabolic surgery and the need to conform to preparatory and discharge guidelines, patients must adhere to
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strict nutritional and diabetes management protocols. Also, the pharmacological regimen that is
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instituted upon discharge is distinct from the preoperative regimen. Oftentimes, the dose for insulin and oral medications are significantly decreased or withdrawn. As time elapses and
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depending on several factors (e.g., exercise adherence), diabetes control becomes tenuous in a
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small portion of the patients because there is weight regain and on-going beta cell failure. At this time interval and in the aforesaid underlying population, intensification of diabetes therapy
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becomes prudent. Indeed, pharmacotherapy from the preoperative to the postoperative phase is
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labile and may be complex. Therefore, by discussing pharmacology options during the
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preoperative, perioperative, and postoperative period, the goal is to guide clinician-driven care.
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Key words: pharmacological therapy; perioperative care; metabolic surgery
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ACCEPTED MANUSCRIPT 1. Introduction Although behavioral modification is a crucial component of type II diabetes (T2D) therapy even after metabolic surgery, convincing a patient to comply with or adhere to a longterm behavioral modification program is an arduous proposition. Even so, T2D is somewhat
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resilient to behavioral and even pharmacological therapy because of the intractability of the disease. As such, the requirement for more efficacious therapeutic options has yielded more
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invasive therapy. Within the past decade, metabolic surgery has been shown to be capable of
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offsetting or reverting some of the deleterious effects of T2D, which is why it has been integrated into the therapeutic armamentarium for T2D. However, the complexity of metabolic
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surgery requires adherence to strict pre and postoperative guidelines. For instance, a very low calorie diet (VLCD) before surgery is often instituted to reduce hepatic steatosis, whilst in the
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postoperative setting the patient’s meal regimen is substantially modified due to the anatomical
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alterations in the gastrointestinal system and the neurohormonal changes that ensue.
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Prior to surgery, adherence to a VLCD will entail the need to modify the anti-diabetic
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regimen. For example, in the days preceding surgery oral hypoglycemic agents are withdrawn, while insulin dose is often reduced by one-half. In contrast, during the perioperative period, an
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insulin regimen will counter the stress-induced hyperglycemic response. With the application of a basal-bolus or insulin infusion regimen, the goal is twofold: neutralize the risk of hypoglycemia and maintain an appropriate blood glucose profile. In doing so, the sequel associated with hypoglycemic and hyperglycemic episodes are minimized.1, 2 Afterwards, the therapeutic potential of metabolic surgery is highlighted by pronounced reductions in weight and hemoglobin A1c (HbA1c) values; oftentimes, diabetes remission is achieved when HbA1c reaches its nadir. During the aforesaid postoperative time interval, 3
ACCEPTED MANUSCRIPT diabetes pharmacotherapy is curtailed; oftentimes, insulin dose is significantly reduced and/or oral agents are withdrawn. However, as time elapses, success is gradually diminished. In the aftermath of the weight loss plateau, there tends to be some relapse as weight regain becomes evident and HbA1c begins to increase. As such, intensification of the anti-diabetes
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pharmacological regimen becomes necessary. Indeed, as illustrated, the prescribed pharmacological regimen during the periods before,
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during, and after metabolic surgery are labile and complex. Therefore, the aim is to provide some
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clarity by highlighting some of the research that has been conducted within the field. Further, some recommendations will be provided to guide clinician-driven care. In doing so, the
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information presented can fill the void present in metabolic surgery care.
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2. Preoperative and inpatient management
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2.1 Very low calorie diet
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Many patients that present to metabolic surgery centers are obese or morbidly obese. As such, they present with hepatosteatosis or steatohepatitis; liver volume is increased which
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obscures the hiatal region. Thus, for the surgeon, creating a small gastric pouch and
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anastomosing the jejunum to the gastric pouch become more cumbersome. Therefore, in preparation for metabolic surgery, clinicians often institute a VLCD to reduce liver volume and intrahepatic fat.3 Empirically, the application of a VLCD has been shown to reduce operative difficulty and postoperative complications.4 A two-week VLCD diet has been demonstrated to be optimal given that, in the aftermath of that time span, further changes in liver volume are considered negligible.5 To attenuate the degree of muscle atrophy, contemporaneous adherence to an exercise regimen may be prudent. Indeed, subjects adhering to a 16-week structured
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ACCEPTED MANUSCRIPT exercise program and a VLCD (1350 kcal/day) derived additional benefits: mitochondrial biogenesis was induced and there were increases in fat oxidation and maximal aerobic capacity.6 With the application of a VLCD and exercise regimen, insulin dose will have to be reduced. Some have recommended that a basal-bolus regimen be reduced by 30% (i.e., basal)
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and 50% (i.e., bolus), respectively.7 Another source suggested decreasing total insulin dose by
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one-half.8 Therefore, total insulin dose may need to be reduced by at least > 50%. However,
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there will be interindividual differences as some patients may require withdrawal while in others
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less significant reductions. For instance, in patients that are well-managed with metformin and a low dose of insulin, insulin injections may cease, while others with severe insulin resistance may
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necessitate less liberal reductions.
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Generally, oral agents that do not engender a significant increase in hypoglycemic risk
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(e.g., metformin) can be maintained. Adherence to long-acting sulfonylureas (SU) are discourage due to the hypoglycemic risk; in contrast, short-acting SU (e.g., glipizide) may impose a lower
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hypoglycemic risk relative to the long-acting variants (Hazard Ratio 2.83 [1.64-4.88]).9
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Therefore, reducing or maintaining SU dose may be more appropriate for the short-acting in comparison to the long-acting variant. In all other instances, oral agents are withheld one day
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prior to surgery.
Monitoring blood glucose levels is pertinent to avoid hypoglycemia especially if the patient is insulin dependent and adhering to a VLCD and exercise regimen. An open line of communication between the patient and clinician during the preoperative period is pertinent because the pharmacological regimen may need to be modified based upon the recorded glucose values. Although glucometer readings are generally less accurate than laboratory-based measures,10 the patient needs to be educated on the importance of maintaining consistency with 5
ACCEPTED MANUSCRIPT their glucose monitoring. Patients should be aware that they may need to validate their prior readings when they are unexpectedly low or high and to couple a glucometer reading with associated symptoms of hypo or hyperglycemia. Some research contends that consistent selfmonitoring improves diabetes management.11
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2.2 Predictors of diabetes remission and inpatient status
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Longer diabetes duration or poorly controlled diabetes, defined as an HbA1c of >7.5%, may be predictive of poor glucose management during the inpatient stay and lower rates of
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diabetes remission.12,13 Thus, clinicians may have an idea as to which patient will require heightened insulin management during the inpatient stay and significant pharmacological dose
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adjustments after surgery.13 Preoperative glucose levels may also portend postoperative weight
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loss outcomes.14 For patient safety, it is imperative to control blood glucose levels in the period
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preceding surgery.2 As such, a target HbA1c of <6.5-7.0% is recommended prior to surgery; patients with long-term diabetes or are poorly controlled can aim to be within 7.0%-8.0%.15 The
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decision on whether to proceed with surgery when an HbA1c >8.0% is delegated to the overlying
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surgeon.15
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2.3 Inpatient and perioperative glucose monitoring During the inpatient stay, glucose monitoring will need to take place upon admission and prior to meals or every 4 to 6 hours if the patient is NPO.16, 17 For patients that require intravenous insulin infusion, glucose monitoring is recommended every 30 to 120 minutes.16 Unless not already done prior or not on file, an HbA1c will need to be conducted to differentiate between individuals with preexisting diabetes versus those without diabetes who are experiencing a stress-induced response to surgery. Maintaining blood glucose levels between
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ACCEPTED MANUSCRIPT 140-180 mg/dL is recommended15, 16; however, as long as the patient is not at significant risk for hypoglycemia when levels drift to 100 mg/dL, premeal and random glucose levels can be < 140 and < 180 mg/dL, respectively.16 Therefore, although 100 mg/dL constitutes the lower threshold, there will be instances when selected low-risk patients may pass the aforementioned threshold
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without undue risk, while others (high-risk) may need to be maintained at over 180 mg/dL.16
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However, diabetes management warrants reassessment when blood glucose levels decline below
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70 mg/dL.16
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For perioperative care, adherence to a subcutaneous rapid acting or continuous insulin infusion regimen is recommended when blood glucose levels are <180 mg/dL but > 140 mg/dL
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and >180 mg/dL, respectively.18 For an insulin infusion protocol, consult the antecedent citation.
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2.4 Insulin therapy
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If the patient was managing their diabetes with longer acting insulins, half of their basal dose may be administered during the morning of surgery.19 Due to the observed three-fold higher
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incidence of hypoglycemia relative to basal-bolus in one study, the use of premixed human
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insulin is not recommended.17, 20 In the aforesaid study, hypoglycemia was more prevalent even though the premixed insulin group received snacks between their main meals; the basal-bolus
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group did not receive snacks. It is unknown if an analogue premixed regimen would have reduced the incidence of hypoglycemia given that it may confer less hypoglycemic risk in relation to a human premixed regimen.21 Subsequently, replacing premixed insulin with another basal regimen (not NPH)22 at half of the premixed dose during the morning of surgery is recommended.19 A basal-bolus, for fasting and mealtime glucose control, plus a correctional element, for hyperglycemic control, insulin paradigm is preferred for inpatient management; adherence to a solitary sliding scale regimen is highly discouraged by the American Diabetes 7
ACCEPTED MANUSCRIPT Association (ADA), and intensive diabetes management is also not advised due to the deleterious effects of hypoglycemia.17 Patients receiving an insulin dose of > 0.6 units/kg are at an increased risk for hypoglycemic events.22 Thus, an inpatient protocol may need to confine the dosage to below the
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aforesaid threshold. Umpierrez et al.23 have spearheaded the research on inpatient diabetes management. As an example of their protocol, if blood glucose levels on admission are between
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140-200 mg/dL, a basal-bolus (insulin glargine and glulisine, respectively) regimen at 0.4
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units/kg/day is recommended; the dose is evenly split (i.e., half) between basal and bolus.23 For a blood glucose level between 201-400 mg/dL, 0.5 units/kg/day were given. Incrementally, if
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fasting glucose was still >140 mg/dL, the basal dose was increased by 20%; supplemental insulin may also be given. Decrease basal insulin by 20% if the patient passes the initial hypoglycemic
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threshold (i.e., <70 mg/dL).23 By adhering to the discussed protocol, there were a miniscule
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number of hypoglycemic incidents (e.g., two in one study). The results can likely be replicated in
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real-world care.23
Further, the aforementioned protocol proved to be superior to sliding scale insulin (SSI)
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in the inpatient setting and before general surgery23, 24; however, basal-bolus versus basal plus
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SSI were equivalent in terms of efficacy.12 Finally, a basal-bolus regimen that was comprised of insulin analogues versus (glargine and glulisine) human insulin (NPH and regular) were equally effective in managing blood glucose levels.25, 26 However, there was a trend towards a greater number of sever hypoglycemic episodes (<40 mg/dL) in the human insulin group.26 Hypoglycemic events have been noted to be higher in patients who adhere to a human insulin regimen. Therefore, insulin analogues are preferred to avoid the sequel linked to hypoglycemic events. The authors acknowledge that wide variability exists with respect diabetes management 8
ACCEPTED MANUSCRIPT during the hospital stay. Thus, if the clinician devises an insulin-based protocol that effectively maintains blood glucose within a normal range, then it is appropriate. 3. Post-surgery management
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3.1 Preface to postoperative care
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After metabolic surgery, insulin sensitivity and secretion are improved and blood glucose
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levels are substantially diminished even before drastic weight loss.27 There is data demonstrating that insulin sensitivity and glycaemia improve equally in RYGB and sleeve gastrectomy13, 28, 29;
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thus, the implications for insulin dosing post-surgery (i.e., the extent of dose reduction) may not
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be disparate for the two procedures. However, the research is contentious as some evidence suggests slight superiority of RYGB in the short-term, but with equivalency being observed
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years later.27, 29, 30 Also, satiety is achieved more readily while hunger is reduced; there is a
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reduced drive to eat calorically dense foods.31 As a consequent, daily caloric intake is diminished
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to around 1000 kcal three months after surgery with gradual increases thereafter.32, 33 Subsequently, the specific antidiabetic regimen that is instituted is influenced by the
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patient’s glycemic status and the specific time point after surgery. Further, while incidence may plateau thereafter, the clinician should bear in mind that there is a rise in the incidence of
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hypoglycemia one year after RYGB relative to baseline.34 The authors noted that a lower age, greater weight loss, and more substantial improvements in beta-cell function predicted hypoglycemic events.34 After the initial sharp decline in blood glucose levels, the number of antidiabetic agents and the dose will be reduced acutely post-surgery. Thereafter, as weight loss progresses and glycated hemoglobin is reduced, further changes will be required. Certainly, the diabetic regimen is labile: it will progress from reinstitution acutely after surgery to withdrawal
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ACCEPTED MANUSCRIPT (i.e., as blood sugar improves) to reincorporation as disease state progresses. To guide diabetes management, an HbA1c will need to be conducted three months post-surgery and intermittently thereafter to delineate the extent of diabetes improvement. As per the ADA, although the target glucose range may be reduced or increased depending on the patient’s state (i.e., acute diabetes
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onset vs. poor diabetes control), a general goal is to attain an HbA1c <7%.35
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3.2 Insulin management and diabetic ketoacidosis after metabolic surgery
In the inpatient setting acutely post-surgery, the patient can be managed with a basal-
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bolus plus corrective insulin regimen. In patient’s that either adhered to a sliding scale (irrespective of insulin therapy status preoperatively) or a SSI and long-acting insulin regimen in
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insulin dependent patient’s, inpatient diabetes control was attained sparingly; principally, 36.3
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and 48.4% of RYGB and sleeve gastrectomy patients, respectively, demonstrated control of their
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blood glucose (defined as <180 mg/dL).36 Implying that a more intensive regimen was needed; therefore, adherence to a basal-bolus or an insulin infusion regimen as needed may be pertinent.
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Caution is advised with respect to type I diabetes (TID) patients after metabolic surgery,
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as drastic reductions in insulin dose may precipitate diabetic ketoacidosis (DKA). For instance, in a small retrospective analysis (case study), DKA was prominent (n=12) in the early
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postoperative time interval (days 0-61; median=12th day).37 Notwithstanding that non-DKA prone individuals were not included in the analysis, one predictive factor may be poor glycemic management in the preoperative period (median HbA1c was 9.3%). Nonspecific symptoms of DKA included abdominal pain, nausea, and vomiting.37 One review corroborated the results of the aforementioned retrospective study. Although the investigators did not pool the DKA frequency, DKA was shown to occur in a review of several case studies (n=107).38 What precipitated DKA was not discussed. Interestingly, even though decrements in HbA1c are 10
ACCEPTED MANUSCRIPT generally not as pronounced in patients with TID (8.3% to 7.6% vs. 8.0% to 5.9% in patients with T2D),39 postoperative insulin dose was reduced by a similar amount: a one-half reduction in most of the included trials.38 Another retrospective study verified the nearly on-half reduction in insulin dose at 6 and 12 months.39 The authors also expressed concern over the increase in
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hypoglycemia at six months post-op.39 Additional research is needed in regards to TID and
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metabolic surgery.
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If the T2D patient requires insulin after discharge, the dose, as demonstrated in the
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retrospective analysis in patients with TID, will have to be reduced. Empirical evidence indicates that among insulin dependent T2D patients, 93% of RYGB and 82% of sleeve gastrectomy
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patients reduced their long-acting insulin dose by greater than 50%, while 90.6% and 100% reduced their short-acting insulin regimen by > 50%, respectively; specifically, the average dose
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for long-acting and short-acting insulin was 10.4 and 1.7 units on discharge.36 At one year, there
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was a further reduction in insulin use; long-acting and short-acting insulin dose was 3.7 (9% of
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patients) and 1.7 units (8.4% of patients), respectively.36 Schauer et al. substantiated the results by noting that 4 and 8% of RYGB and sleeve gastrectomy patients were insulin dependent at 12
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months, respectively; at three years, the results were essentially identical, while there was a
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marginal increase to 12 and 11% at five years, respectively.29, 30, 40 Therefore, the insulin dose will need to be titrated downwards for at least up to 12 months post-surgery with a significant reduction occurring during the first month.41 The data at three and five years affirms the significant durability and efficacy of the two surgery subtypes in maintaining adequate glucose control (HbA1c ~ 7.4%) without the need for insulin therapy. Consequently, for patients receiving < 30 units of basal insulin before surgery, the dose can be withdrawn, but short-acting insulin may be used to manage postprandial glucose levels.8 11
ACCEPTED MANUSCRIPT In patients using > 30 units of basal insulin preoperatively, doses were attenuated by 50-80%.8 However, recommending and applying a one-size-fits-all insulin prescription is not feasible given the wide array of clinical presentations. Thus, recommendations should viewed as a template and not as rigid prescription for each patient. There will need to be an appropriate
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follow-up schedule in place to monitor the effectiveness of an anti-hyperglycemic regimen.
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3.3 Oral therapy
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associated fall and fracture risk with insulin therapy.42, 43
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Moreover, due to hypoglycemic events, it is important that the physician be cognizant of the
Beyond the observation that RYGB (relative to sleeve gastrectomy) patients may achieve
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T2D remission without the need for concurrent pharmacotherapy,30 studies investigating the
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effects of medicinal products after bariatric surgery are scarce. Given that an individualized
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approach will be required for each patient and be affected by the underlying surgery type, the purpose is not to advocate for a specific pharmacological regimen after metabolic surgery.
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Furthermore, a holistic review of all the potential pharmacological aids and their side effects is
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beyond the scope of the review. In general, an oral pharmacotherapy regimen that facilitates weight loss and euglycemia, while also conferring a low hypoglycemic risk is optimal.
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There are two distinct and relevant time points after metabolic surgery: acutely postsurgery and long-term after surgery. In the acute phase and upon discharge, the recommendation is that metformin, unless contraindicated, can be reinstituted as a stand-alone therapy when HbA1c is <9%15, 35; the dose will depend on the extent of glucose control and, if any, the associated side effects. The clinician may consider an additional agent if the patient is still refractory to treatment (e.g., HbA1c is 8.5%). Also, when HbA1c is >9%, a second agent can be coupled with metformin that facilitates weight loss and/or cardiovascular risk reduction in 12
ACCEPTED MANUSCRIPT selected at-risk individuals35; the agent may need to have neutral or positive effects on bone mineral density and fall risk given that, after metabolic surgery, fracture risk and BMD may be exacerbated.44-46 Consequently, prescribing thiazolidinediones are not recommended because of their negative effects on BMD.47, 48 In addition, notwithstanding the possible neutral effects on
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bone,49, 50 prescription of long-acting SU are discouraged15; the short-acting variants may be
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has generally been noted to exert positive effects on bone.51
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more suitable due to the purported lower hypoglycemic risk.9 It is worth noting that metformin
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Ultimately, as disease state progresses and weight regain becomes more prominent in a small segment of the population, the long-term approach shifts to coupling metformin with a
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pharmacological agent that has more pleiotropic effects: cardiovascular risk reduction, weight
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loss, and improved renal outcomes. As a second-tier form of therapy, there are three agents that fulfill the aforesaid criteria and may have neutral or beneficial effects on bone: the sodium-
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glucose cotransporter-2 (SGL2) inhibitors canagliflozin (neutral) and empagliflozin (neutral) and
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the glucagon-like peptide 1 (GLP-1) analogue liraglutide (beneficial).52-55
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Indeed, long-term randomized controlled trials have demonstrated improved cardiovascular and renal outcomes and reductions in all-cause mortality in the case of
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empagliflozin.56-58 The beneficial outcomes may signify a class effect and be mediated by the aggregate effect on a myriad of parameters: improvements in blood pressure, weight (~ 3 kg), lipids, and blood glucose levels. Moreover, although other medications likely exert a similar effect,59, 60 liraglutide or canagliflozin may, at the very least, stagnate the perpetual deterioration in B-cell function by attenuating the effects of glucotoxicity.59, 61, 62 However, amelioration of Bcell function may be more pronounced with liraglutide relative to insulin or exenatide.61, 62
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ACCEPTED MANUSCRIPT Possibly inferring that liraglutide improved the purported irreversible modulator of B-cell function: B-cell preservation.61 In addition, both classes of medication confer a low hypoglycemic risk. While canagliflozin is well-known to exhibit a low hypoglycemic profile,63 for liraglutide, the
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LEADER and other investigators observed a lower hypoglycemic incidence relative to placebo
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or glimepiride.57, 64 Canagliflozin’s effects are independent of insulin secretion given that it
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facilitates glucose excretion via the kidneys; the threshold for urinary glucose excretion is
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diminished to a safe range that overlies the level typified by hypoglycemia.63 However, the downside of GLP-1 analogues and SGL2 inhibitors are their possible side
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effects. For canagliflozin, the primary side effects include increased urination and thirst,
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dehydration, urinary tract infections, and genital yeast infections.63 The latter two side effects are
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more prevalent in women.63 It is unknown if side effect frequency is increased in patients who have underwent metabolic surgery. For instance, given the already exaggerated incretin response
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post-surgery, it is to be elucidated if a GLP-1 analogues may further compound hypoglycemic risk or gastrointestinal side effects. However, with respect to liraglutide, if gastrointestinal side
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effects do occur, their frequency may diminish with time.62 In addition, relative to short-acting
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variants, long-acting GLP-1 analogues may be more appropriate for patients who underwent metabolic surgery because of the improved outcomes and the diminished side effect frequency.62 While both treatments groups had similar weight loss outcomes (-3.24 [liraglutide] vs. 2.87 kg [exenatide]), HbA1c decreased more significantly (1.12% versus 0.79%) and side effects (nausea and hypoglycemia) were less common in the liraglutide group.62 Albeit retrospective in design, one trial, which is discussed in the ensuing paragraph, has shown promising results with liraglutide treatment in patients who have underwent metabolic surgery. 14
ACCEPTED MANUSCRIPT Interestingly, in addition to fostering weight loss,65 liraglutide was shown to be well tolerated by post-metabolic surgery patients.66 Specifically, in a miniscule heterogeneous sample (n=15) that mainly comprised of RYGB patients (53%), hypoglycemia occurred in 6.7% of the subjects; also, the prevalence of nausea and vomiting was 35.8% and 21.1% at three months,
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respectively.66 Importantly, at baseline, the proportion of patients with an HbA1c of <7% was
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66.7% which improved to 81.8% after treatment with liraglutide. It would be interesting if the
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results can be corroborated in additional studies and whether they can be extrapolated to other
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pharmacological classes such as SGL2 inhibitors.
Such agents that confer a myriad of positive effects may be well suited for patients who
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have underwent metabolic surgery. Principally, with metabolic surgery, not only can patients
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reduce their number of comorbidities, but they can possibly further sustain the positive outcomes with the additive effects of SGL2 or GLP-1 on cardiovascular risk and weight loss. Therefore,
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some have advocated that the concomitant effects of metabolic surgery and a SGL2 inhibitor or a
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long-acting GLP-1 analogue may be highly therapeutic for patients with T2D; given that the positive effects of metabolic surgery subside with time, an SGL2 inhibitor or GLP-1 analogue
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may extend the durability of the positive outcomes by fostering weight loss and cardiovascular
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risk reduction (etc.). As opposed to the traditional emphasis on using metformin as the primary monotherapy, a regimen that couples metabolic surgery with either of the aforementioned classes of medication (SGL2 or GLP-1) represents a contemporary view on diabetes management. Indubitably, other SGL2 inhibitors, long-acting GLP-1 analogues, and dipeptidyl peptidase-4 inhibitors warrant consideration. Additional research will be required to justify their prescription over other pharmacological aids.
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Figure 1. Medical management of diabetes in metabolic surgery patients Preoperative and Postoperative Recommendations Preoperative Oral
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Insulin
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-
Oral
Postoperative
- Reincorporate metformin (A1c <9%) - Add incretin, DPP-4, or glucose inhibitor (A1c >9%) - Subject to inquiry: introduce incretin analogued or glucose inhibitor as stand-alone therapy after discharge (A1c <9%)
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- Withdraw long-acting - Decrease dose by Sulfonylurea about 50%a - Maintain or reduce - Nonhuman insulin glucose inhibitor, is recommended c metformin, incretin, or DPP-4 inhibitor dose
Insulin
- Decrease overall dose by about 50%b - Human insulin is not recommended - Dose may have to be titrated down for up to 12 months - Premixed insulin may heighten hypoglycemic risk
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Dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitors). (a) When instituting a very low calorie diet at least two weeks prior to surgery; (b) insulin dose is relative to preoperative dose and before a very low calorie diet. (c) Due to associated hypoglycemic risk, human insulin is not advised. (d) Long-acting incretin analogue is suggested.
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Table 1. Additional considerations and recommendations Preoperatively 1. Try to implement an exercise regimen with a very low calorie diet to offset decreases in lean muscle mass. Note that total caloric intake may need to be increased slightly as a result. 2. Maintain some communication with the patient to help reduce the incidence of hypoglycemia and to facilitate adherence. 3. If the patient is more poorly controlled, then they will likely necessitate a more intensive insulin regimen during the inpatient stay. Further, the implications for medication withdrawal and/or reincorporation, in the postoperative period, will be different than for those who are more optimally controlled. Thus, preparation can begin during the preoperative period. Perioperative and inpatient setting 1. Implement an insulin protocol that minimizes the risk of hypoglycemia and hyperglycemia. 2. Depending on the patient’s state, a continuous infusion or rapid acting insulin regimen are recommended during perioperative period.18 3. Monitor blood glucose levels diligently. 4. Prepare for and refine patient-specific discharge guidelines. Postoperatively 1. Have the patient meet with a multidisciplinary team if possible. For instance, appropriate follow-up with the surgeon, endocrinologist, dietician, and if possible a trained fitness professional is recommended. 2. Exercise and dietary adherence is advised for more favorable and durable outcomes.
3.4 Pharmacokinetics and pharmacodynamics after metabolic surgery
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Given the gastrointestinal adaptations that ensue, pharmacokinetics and/or pharmacodynamics may be influenced. For example, metformin’s bioavailability was paradoxically shown to be improved in subjects who underwent RYGB > 3 months prior to commencing the study.67 Another study also demonstrated that RYGB subjects who had surgery greater than one year ago had an improved pharmacokinetic profile; time from ingestion to maximal concentration was truncated for each of the constituent substances in an ingested cocktail: caffeine, tolbutamide, omeprazole, and midazolam.68 17
ACCEPTED MANUSCRIPT Whether there is an improvement or a decrement in gastric emptying is subject to further inquiry,69 but in either case metabolic surgery likely has an effect on drug pharmacokinetics; moreover, intestinal transit time or intestinal adaptations may elicit an alteration in drug pharmacokinetics/dynamics.67, 68 The relative time point (i.e., acutely or long-term after surgery)
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when a pharmacokinetic/pharmacodynamic study is undertaken may also be pertinent as
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intestinal adaptations may not manifest shortly after surgery.68 Further, gastric pH may also
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affect drug digestion given that pH is increased in RYGB subjects.70 The study of the effects of metabolic surgery on pharmacokinetics/dynamics is in its infancy and its possible effects are
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4. Conclusion and future considerations
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strictly conjecture at this time given the lack of evidence.
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First and foremost, we do not wish to imply that all patients who undergo metabolic
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surgery experience suboptimal results in the long-term. Indeed, this is not true as only a small portion of the population may have diabetes relapse and experience weight regain. We cannot
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emphasize enough that even if the patient experiences weight regain, the positive effects are still
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drastic in comparison to baseline and in relation to other forms of therapy. When guiding care, the clinician should be cognizant of the effects of varying metabolic
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surgery procedures. For example, without the concomitant need for oral therapy, RYGB has substantial effects on diabetes remission; thus, patients undergoing RYGB may require their pharmacotherapy regimen be fine-tuned more substantially. Along the same lines, diabetes history and extent of control have implications on inpatient and postoperative care. Patients who are poorly controlled in the preoperative period may require more intensive insulin dosing regimens perioperatively and predict lower rates of diabetes remission postoperatively. Therefore, they are less likely to be weaned off their oral therapy. 18
ACCEPTED MANUSCRIPT As pragmatic advice, patients should be screened appropriately and educated on the benefits and risks of metabolic surgery. They must have realistic expectations before proceeding with surgery. Even though metabolic surgery fosters drastic weight loss outcomes, a majority of the patients will still be obese.
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A large portion of the cited evidence comes from ancillary fields and, therefore, is not necessarily metabolic surgery specific. There are a myriad of areas within the umbrella of
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metabolic surgery care that require further research: pharmacodynamics/pharmacokinetics after
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surgery, inpatient and perioperative glucose management, and pre and postoperative insulin dosing requirements. In addition, delineating an optimal oral therapy regimen after metabolic
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surgery requires further study.
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Acknowledgements: N/A
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Funding source: N/A
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Conflict of interest: The authors report no conflicts of interest.
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ACCEPTED MANUSCRIPT References
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1. Turchin A, Matheny M, Shubina M, Scanlon J, Greenwood B, Pendergrass M. Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward. Diabetes Care. 2009;32(7): 1153-1157. 2. Noordzij P, Boersma E, Schreiner F, et al. Increased preoperative glucose levels are associated with perioperative mortality in patients undergoing noncardiac, nonvascular surgery. European Journal of Endocrinology. 2007;156(1): 137-142. 3. Edholm D, Kullberg J, Haenni A, et al. Preoperative 4-week low-calorie diet reduces liver volume and intrahepatic fat, and facilitates laparoscopic gastric bypass in morbidly obese. Obesity Surgery. 2011;21(3): 345-350. 4. van Nieuwenhove Y, Dambrauskas Z, Campillo-Soto A, et al. Preoperative very low-calorie diet and operative outcome after laparoscopic gastric bypass: a randomized multicenter study. Archives of Surgery. 2011;146(11): 1300-1305. 5. Edholm D, Kullberg J, Karlsson F, Haenni A, Ahlström H, Sundbom M. Changes in liver volume and body composition during 4 weeks of low calorie diet before laparoscopic gastric bypass. Surgery of Obesity and Related Diseases. 2015;11(3): 602-606. 6. Snel M, Gastaldelli A, Ouwens D, et al. Effects of adding exercise to a 16-week very low-calorie diet in obese, insulin-dependent type 2 diabetes mellitus patients. Journal of Clinical Endocrinology and Metabolism. 2012;97(7): 2512-2520. 7. Thorell A, Hagström-Toft E. Treatment of diabetes prior to and after bariatric surgery. Journal of diabetes Science and Technology. 2012;6(5): 1226-1232. 8. Bland C, Tritsch A, Bookstaver D, Sweeney L, Wiley D, Choi Y. Hypertension and diabetes mellitus medication management in sleeve gastrectomy patients. American Journal of Health-System Pharmacy. 2013;70(12): 1018-1020. 9. Douros A, Yin H, Yu O, Filion K, Azoulay L, Suissa S. Pharmacologic differences of sulfonylureas and the risk of adverse cardiovascular and hypoglycemic events. Diabetes Care. 2017;40(11): 1506-1513. 10. Dungan K, Chapman J, Braithwaite S, J B. Glucose measurement: confounding issues in setting targets for inpatient management. Diabetes Care. 2007;30(2): 403-409. 11. Elgart J, González L, Prestes M, Rucci E, Gagliardino J. Frequency of self-monitoring blood glucose and attainment of HbA1c target values. Acta Diabetologica. 2016;53(1): 57-62. 12. Umpierrez G, Smiley D, Hermayer K, et al. Randomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial. Diabetes Care. 2013;36(8): 2169-2174. 13. Nannipieri M, Baldi S, Mari A, et al. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. Journal of Clinical Endocrinology and Metabolism. 2013;98(11): 4391-4399. 14. Perna M, Romagnuolo J, Morgan K, Byrne T, Baker M. Preoperative hemoglobin A1c and postoperative glucose control in outcomes after gastric bypass for obesity. Surgery of Obesity and Related Diseases. 2012;8(6): 685-690. 15. Mechanick J, Youdim A, Jones D, 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. Endocrine Practice. 2013;19(2): 337-372. 16. Moghissi E, Korytkowski M, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;15(4): 353-369. 20
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17. Association AD. Diabetes care in the hospital. Diabetes Care. 2017;40(1): S120-S127. 18. Smiley D, Umpierrez G. Perioperative glucose control in the diabetic or nondiabetic patient. Southern Medical Journal. 2006;99(6): 580-589. 19. Duncan A. Hyperglycemia and perioperative glucose management. Current Pharmaceutical Design. 2012;18(38): 6195-6203. 20. Bellido V, Suarez L, Rodriguez M, et al. Comparison of basal-bolus and premixed insulin regimens in hospitalized patients with type 2 diabetes. Diabetes Care. 2015;38(12): 2211-2216. 21. Boehm B, Vaz J, Brøndsted L, Home P. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. European Journal Of Internal Medicine. 2004;15(8): 496-502. 22. Rubin D, Rybin D, Doros G, McDonnell M. Weight-based, insulin dose-related hypoglycemia in hospitalized patients with diabetes. Diabetes Care. 2011;34(8): 1723-1728. 23. Umpierrez G, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Daibetes Care. 2007;30(9): 2181-2186. 24. Umpierrez G, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Daibetes Care. 2011;34(2): 256-261. 25. Umpierrez G, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism. 2009;94(2): 564-569. 26. Bueno E, Benitez A, Rufinelli J, et al. Basal-Bolus regimen with insulin analogues versus human insulin in medical patients with type 2 diabetes: A randomized controlled trial in Latin America. Endocrine Practice. 2015;21(7): 807-813. 27. Kashyap SR, Daud S, Kelly KR, et al. Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes. International Journal of Obesity. 2010;34(3): 462-471. 28. Benaiges D, Flores Le-Roux J, Pedro-Botet J, et al. Sleeve gastrectomy and Roux-en-Y gastric bypass are equally effective in correcting insulin resistance. International Journal of Surgery. 2013;11(4): 309-313. 29. Schauer P, Bhatt D, Kirwan J, et al. Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. The New England Journal of Medicine. 2017;376(7): 641-651. 30. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. New England Journal of Medicine. 2012;366(17): 1567-1576. 31. Ullrich J, Ernst B, Wilms B, Thurnheer M, Schultes B. Roux-en Y gastric bypass surgery reduces hedonic hunger and improves dietary habits in severely obese subjects. Obesity Surgery. 2013;23(1): 5055. 32. Giusti V, Theytaz F, Di Vetta V, Clarisse M, Suter M, Tappy L. Energy and macronutrient intake after gastric bypass for morbid obesity: a 3-y observational study focused on protein consumption. The American Journal of Clinical Nutrition. 2016;103(1): 18-24. 33. Coluzzi I, Raparelli L, Guarnacci L, et al. Food intake and changes in eating behavior after laparoscopic sleeve gastrectomy. Obesity Surgery. 2016;26(9): 2059-2067. 34. Raverdy V, Baud G, Pigeyre M, et al. Incidence and predictive factors of postprandial hyperinsulinemic hypoglycemia after roux-en-y gastric bypass: A five year longitudinal study. Annals of Surgery. 2016;264(5): 878-885. 35. Association AD. 6. Glycemic targets: Standards of medical care in diabetes-2018. Daibetes Care. 2018;41(1): S55-S64.
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36. Zaman J, Shah N, Leverson G, Greenberg J, Funk L. The effects of optimal perioperative glucose control on morbidly obese patients undergoing bariatric surgery. Surgical Endoscopy. 2017;31(3): 14071413. 37. Aminian A, Kashyap S, Burguera B, et al. Incidence and clinical reatures of diabetic ketoacidosis after bariatric and metabolic surgery. Diabetes Care. 2016;39(4): e50-e53. 38. Kirwan J, Aminian A, Kashyap S, Burguera B, Brethauer S, Schauer P. Bariatric surgery in obese patients with type 1 diabetes. Diabetes Care. 2016;39(6): 941-948. 39. Faucher P, Poitou C, Carette C, et al. Bariatric surgery in obese patients with type 1 diabetes: effects on weight loss and metabolic control. Obesity Surgery. 2016;26(10): 2370-2378. 40. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. New England Journal of Medicine. 2014;370(21): 2002-2013. 41. Tritsch A, Bland C, Hatzigeorgiou C, Sweeney L, Phillips M. A retrospective review of the medical management of hypertension and diabetes mellitus following sleeve gastrectomy. Obesity Surgery. 2015;25(4): 642-647. 42. Wallander M, Axelsson K, Nilsson A, Lundh D, Lorentzon M. Type 2 diabetes and risk of hip fractures and non-skeletal fall injuries in the elderly: A study rrom the rractures and fall injuries in the elderly cohort (FRAILCO). Journal of Bone and Mineral Research. 2017;32(3): 449-460. 43. Schwartz A, Hillier T, Sellmeyer D, et al. Older women with diabetes have a higher risk of falls: a prospective study. Daibetes Care. 2002;25(10): 1749-1754. 44. Yu E, Bouxsein M, Putman M, et al. Two-year changes in bone density after Roux-en-Y gastric bypass surgery. Journal of Clinical Endocrinology and Metabolism. 2015;100(4): 1452-1459. 45. Shanbhogue V, Støving R, Frederiksen K, et al. Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: a two-year longitudinal study. European Journal of Endocrinology. 2017;176(6): 685-693. 46. Yu E, Lee M, Landon J, Lindeman K, Kim S. Fracture risk after bariatric surgery: Roux-en-Y gastric bypass versus adjustable gastric banding. Journal of Bone and Mineral Research. 2017;32(6): 1229-1236. 47. Ali A, Weinstein R, Stewart S, Parfitt A, Manolagas S, Jilka R. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005;146(3): 12261235. 48. Lecka-Czernik B, Ackert-Bicknell C, Adamo M, et al. Activation of peroxisome proliferatoractivated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Bone. 2007;148(2): 903-911. 49. Zinman B, Haffner S, Herman W, et al. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism. 2010;95(1): 134-142. 50. Vianna A, de Lacerda C, Pechmann L, et al. Vildagliptin has the same safety profile as a sulfonylurea on bone metabolism and bone mineral density in post-menopausal women with type 2 diabetes: a randomized controlled trial. Diabetology & Metabolic Syndrome. 2017;9. 51. Marycz K, Tomaszewski K, Kornicka K, et al. Metformin decreases reactive oxygen species, enhances osteogenic properties of adipose-derived multipotent mesenchymal stem cells in vitro, and increases bone density In vivo. Oxidative Medicine and Cellular Longevity. 2016;2016. 52. Watts N, Bilezikian J, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism. 2016;101(1): 157-166. 53. Henriksen D, Alexandersen P, Hartmann B, et al. Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone. 2009;45(5): 833-842.
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54. Iepsen E, Lundgren J, Hartmann B, et al. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. Journal of Clinical Endocrinology and Metabolism. 2015;100(8): 2909-2917. 55. Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. 2015;373(22): 2117-2128. 56. Neal B, Perkovic V, Mahaffey K, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. The New England Journal of Medicine. 2017;377(7): 644-657. 57. Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016;375(4): 311-322. 58. Mann J, Ørsted D, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. New England Journal of Medicine. 2017;377(9): 839-848. 59. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014;57(5): 891-901. 60. Meier J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nature Reviews Endocrinology. 2012;8(12): 728-742. 61. Retnakaran R, Kramer C, Choi H, Swaminathan B, Zinman B. Liraglutide and the preservation of pancreatic β-cell function in early type 2 diabetes: the LIBRA trial. Diabetes Care. 2014;37(12): 32703278. 62. Buse J, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683): 39-47. 63. Seufert J. SGLT2 inhibitors - an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8: 543-554. 64. Østoft S, Bagger J, Hansen T, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7): 1797-1805. 65. Creange C, Lin E, Ren-Fielding C, Lofton H. Use of liraglutide for weight loss in patients with prior bariatric surgery. Surgery for Obesity and Related Diseases. 2016;12(7): S157 66. Gorgojo-Martínez J, Feo-Ortega G, Serrano-Moreno C. Effectiveness and tolerability of liraglutide in patients with type 2 diabetes mellitus and obesity after bariatric surgery. Surgery of Obesity and Related Diseases. 2016;12(10): 1856-1863. 67. Padwal R, Gabr R, Sharma A, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011;34(6): 1295-1300. 68. Tandra S, Chalasani N, Jones D, Mattar S, Hall S, Vuppalanchi R. Pharmacokinetic and pharmacodynamic alterations in the Roux-en-Y gastric bypass recipients. Annals of Surgery. 2013;258(2): 262-269. 69. Miras A, le Roux C. Mechanisms underlying weight loss after bariatric surgery. Nature Reviews Gastroenterology & Hepatology. 2013;10(10): 575-584. 70. Geraldo M, Fonseca F, Gouveia M, Feder D. The use of drugs in patients who have undergone bariatric surgery. Int J Gen Med. 2014;7: 219-224.
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Karim G. Kheniser, Sangeeta R. Kashyap PII: DOI: Reference:
S1056-8727(18)30552-X doi:10.1016/j.jdiacomp.2018.06.006 JDC 7226
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
16 May 2018 6 June 2018 7 June 2018
Please cite this article as: Karim G. Kheniser, Sangeeta R. Kashyap , Diabetes management before, during, and after bariatric and metabolic surgery. Jdc (2018), doi:10.1016/ j.jdiacomp.2018.06.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Diabetes management before, during, and after bariatric and metabolic surgery Karim G. Khenisera and Sangeeta R. Kashyapa Department of Endocrinology and Metabolism, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, U.S.a
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Email: [email protected]
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[email protected]
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Address correspondence to: Sangeeta R. Kashyap MD Professor of Medicine 9500 Euclid Ave. (F-20) Cleveland, OH, 44195 Phone: 216-445-2679 Email: [email protected] Fax: 216-445-1656
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ACCEPTED MANUSCRIPT Abstract Metabolic surgery is unrivaled by other therapeutic modalities due to its ability to foster diabetes remission. Metabolic surgery is an integral therapeutic modality in the obese and morbidly obese populations because pharmacological and behavioral therapy often fail to effectively manage
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type II diabetes over the long run. However, given the relative invasiveness of the metabolic surgery and the need to conform to preparatory and discharge guidelines, patients must adhere to
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strict nutritional and diabetes management protocols. Also, the pharmacological regimen that is
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instituted upon discharge is distinct from the preoperative regimen. Oftentimes, the dose for insulin and oral medications are significantly decreased or withdrawn. As time elapses and
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depending on several factors (e.g., exercise adherence), diabetes control becomes tenuous in a
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small portion of the patients because there is weight regain and on-going beta cell failure. At this time interval and in the aforesaid underlying population, intensification of diabetes therapy
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becomes prudent. Indeed, pharmacotherapy from the preoperative to the postoperative phase is
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labile and may be complex. Therefore, by discussing pharmacology options during the
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preoperative, perioperative, and postoperative period, the goal is to guide clinician-driven care.
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Key words: pharmacological therapy; perioperative care; metabolic surgery
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ACCEPTED MANUSCRIPT 1. Introduction Although behavioral modification is a crucial component of type II diabetes (T2D) therapy even after metabolic surgery, convincing a patient to comply with or adhere to a longterm behavioral modification program is an arduous proposition. Even so, T2D is somewhat
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resilient to behavioral and even pharmacological therapy because of the intractability of the disease. As such, the requirement for more efficacious therapeutic options has yielded more
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invasive therapy. Within the past decade, metabolic surgery has been shown to be capable of
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offsetting or reverting some of the deleterious effects of T2D, which is why it has been integrated into the therapeutic armamentarium for T2D. However, the complexity of metabolic
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surgery requires adherence to strict pre and postoperative guidelines. For instance, a very low calorie diet (VLCD) before surgery is often instituted to reduce hepatic steatosis, whilst in the
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postoperative setting the patient’s meal regimen is substantially modified due to the anatomical
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alterations in the gastrointestinal system and the neurohormonal changes that ensue.
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Prior to surgery, adherence to a VLCD will entail the need to modify the anti-diabetic
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regimen. For example, in the days preceding surgery oral hypoglycemic agents are withdrawn, while insulin dose is often reduced by one-half. In contrast, during the perioperative period, an
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insulin regimen will counter the stress-induced hyperglycemic response. With the application of a basal-bolus or insulin infusion regimen, the goal is twofold: neutralize the risk of hypoglycemia and maintain an appropriate blood glucose profile. In doing so, the sequel associated with hypoglycemic and hyperglycemic episodes are minimized.1, 2 Afterwards, the therapeutic potential of metabolic surgery is highlighted by pronounced reductions in weight and hemoglobin A1c (HbA1c) values; oftentimes, diabetes remission is achieved when HbA1c reaches its nadir. During the aforesaid postoperative time interval, 3
ACCEPTED MANUSCRIPT diabetes pharmacotherapy is curtailed; oftentimes, insulin dose is significantly reduced and/or oral agents are withdrawn. However, as time elapses, success is gradually diminished. In the aftermath of the weight loss plateau, there tends to be some relapse as weight regain becomes evident and HbA1c begins to increase. As such, intensification of the anti-diabetes
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pharmacological regimen becomes necessary. Indeed, as illustrated, the prescribed pharmacological regimen during the periods before,
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during, and after metabolic surgery are labile and complex. Therefore, the aim is to provide some
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clarity by highlighting some of the research that has been conducted within the field. Further, some recommendations will be provided to guide clinician-driven care. In doing so, the
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information presented can fill the void present in metabolic surgery care.
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2. Preoperative and inpatient management
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2.1 Very low calorie diet
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Many patients that present to metabolic surgery centers are obese or morbidly obese. As such, they present with hepatosteatosis or steatohepatitis; liver volume is increased which
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obscures the hiatal region. Thus, for the surgeon, creating a small gastric pouch and
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anastomosing the jejunum to the gastric pouch become more cumbersome. Therefore, in preparation for metabolic surgery, clinicians often institute a VLCD to reduce liver volume and intrahepatic fat.3 Empirically, the application of a VLCD has been shown to reduce operative difficulty and postoperative complications.4 A two-week VLCD diet has been demonstrated to be optimal given that, in the aftermath of that time span, further changes in liver volume are considered negligible.5 To attenuate the degree of muscle atrophy, contemporaneous adherence to an exercise regimen may be prudent. Indeed, subjects adhering to a 16-week structured
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ACCEPTED MANUSCRIPT exercise program and a VLCD (1350 kcal/day) derived additional benefits: mitochondrial biogenesis was induced and there were increases in fat oxidation and maximal aerobic capacity.6 With the application of a VLCD and exercise regimen, insulin dose will have to be reduced. Some have recommended that a basal-bolus regimen be reduced by 30% (i.e., basal)
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and 50% (i.e., bolus), respectively.7 Another source suggested decreasing total insulin dose by
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one-half.8 Therefore, total insulin dose may need to be reduced by at least > 50%. However,
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there will be interindividual differences as some patients may require withdrawal while in others
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less significant reductions. For instance, in patients that are well-managed with metformin and a low dose of insulin, insulin injections may cease, while others with severe insulin resistance may
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necessitate less liberal reductions.
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Generally, oral agents that do not engender a significant increase in hypoglycemic risk
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(e.g., metformin) can be maintained. Adherence to long-acting sulfonylureas (SU) are discourage due to the hypoglycemic risk; in contrast, short-acting SU (e.g., glipizide) may impose a lower
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hypoglycemic risk relative to the long-acting variants (Hazard Ratio 2.83 [1.64-4.88]).9
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Therefore, reducing or maintaining SU dose may be more appropriate for the short-acting in comparison to the long-acting variant. In all other instances, oral agents are withheld one day
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prior to surgery.
Monitoring blood glucose levels is pertinent to avoid hypoglycemia especially if the patient is insulin dependent and adhering to a VLCD and exercise regimen. An open line of communication between the patient and clinician during the preoperative period is pertinent because the pharmacological regimen may need to be modified based upon the recorded glucose values. Although glucometer readings are generally less accurate than laboratory-based measures,10 the patient needs to be educated on the importance of maintaining consistency with 5
ACCEPTED MANUSCRIPT their glucose monitoring. Patients should be aware that they may need to validate their prior readings when they are unexpectedly low or high and to couple a glucometer reading with associated symptoms of hypo or hyperglycemia. Some research contends that consistent selfmonitoring improves diabetes management.11
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2.2 Predictors of diabetes remission and inpatient status
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Longer diabetes duration or poorly controlled diabetes, defined as an HbA1c of >7.5%, may be predictive of poor glucose management during the inpatient stay and lower rates of
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diabetes remission.12,13 Thus, clinicians may have an idea as to which patient will require heightened insulin management during the inpatient stay and significant pharmacological dose
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adjustments after surgery.13 Preoperative glucose levels may also portend postoperative weight
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loss outcomes.14 For patient safety, it is imperative to control blood glucose levels in the period
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preceding surgery.2 As such, a target HbA1c of <6.5-7.0% is recommended prior to surgery; patients with long-term diabetes or are poorly controlled can aim to be within 7.0%-8.0%.15 The
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decision on whether to proceed with surgery when an HbA1c >8.0% is delegated to the overlying
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surgeon.15
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2.3 Inpatient and perioperative glucose monitoring During the inpatient stay, glucose monitoring will need to take place upon admission and prior to meals or every 4 to 6 hours if the patient is NPO.16, 17 For patients that require intravenous insulin infusion, glucose monitoring is recommended every 30 to 120 minutes.16 Unless not already done prior or not on file, an HbA1c will need to be conducted to differentiate between individuals with preexisting diabetes versus those without diabetes who are experiencing a stress-induced response to surgery. Maintaining blood glucose levels between
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ACCEPTED MANUSCRIPT 140-180 mg/dL is recommended15, 16; however, as long as the patient is not at significant risk for hypoglycemia when levels drift to 100 mg/dL, premeal and random glucose levels can be < 140 and < 180 mg/dL, respectively.16 Therefore, although 100 mg/dL constitutes the lower threshold, there will be instances when selected low-risk patients may pass the aforementioned threshold
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without undue risk, while others (high-risk) may need to be maintained at over 180 mg/dL.16
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However, diabetes management warrants reassessment when blood glucose levels decline below
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70 mg/dL.16
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For perioperative care, adherence to a subcutaneous rapid acting or continuous insulin infusion regimen is recommended when blood glucose levels are <180 mg/dL but > 140 mg/dL
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and >180 mg/dL, respectively.18 For an insulin infusion protocol, consult the antecedent citation.
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2.4 Insulin therapy
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If the patient was managing their diabetes with longer acting insulins, half of their basal dose may be administered during the morning of surgery.19 Due to the observed three-fold higher
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incidence of hypoglycemia relative to basal-bolus in one study, the use of premixed human
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insulin is not recommended.17, 20 In the aforesaid study, hypoglycemia was more prevalent even though the premixed insulin group received snacks between their main meals; the basal-bolus
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group did not receive snacks. It is unknown if an analogue premixed regimen would have reduced the incidence of hypoglycemia given that it may confer less hypoglycemic risk in relation to a human premixed regimen.21 Subsequently, replacing premixed insulin with another basal regimen (not NPH)22 at half of the premixed dose during the morning of surgery is recommended.19 A basal-bolus, for fasting and mealtime glucose control, plus a correctional element, for hyperglycemic control, insulin paradigm is preferred for inpatient management; adherence to a solitary sliding scale regimen is highly discouraged by the American Diabetes 7
ACCEPTED MANUSCRIPT Association (ADA), and intensive diabetes management is also not advised due to the deleterious effects of hypoglycemia.17 Patients receiving an insulin dose of > 0.6 units/kg are at an increased risk for hypoglycemic events.22 Thus, an inpatient protocol may need to confine the dosage to below the
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aforesaid threshold. Umpierrez et al.23 have spearheaded the research on inpatient diabetes management. As an example of their protocol, if blood glucose levels on admission are between
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140-200 mg/dL, a basal-bolus (insulin glargine and glulisine, respectively) regimen at 0.4
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units/kg/day is recommended; the dose is evenly split (i.e., half) between basal and bolus.23 For a blood glucose level between 201-400 mg/dL, 0.5 units/kg/day were given. Incrementally, if
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fasting glucose was still >140 mg/dL, the basal dose was increased by 20%; supplemental insulin may also be given. Decrease basal insulin by 20% if the patient passes the initial hypoglycemic
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threshold (i.e., <70 mg/dL).23 By adhering to the discussed protocol, there were a miniscule
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number of hypoglycemic incidents (e.g., two in one study). The results can likely be replicated in
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real-world care.23
Further, the aforementioned protocol proved to be superior to sliding scale insulin (SSI)
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in the inpatient setting and before general surgery23, 24; however, basal-bolus versus basal plus
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SSI were equivalent in terms of efficacy.12 Finally, a basal-bolus regimen that was comprised of insulin analogues versus (glargine and glulisine) human insulin (NPH and regular) were equally effective in managing blood glucose levels.25, 26 However, there was a trend towards a greater number of sever hypoglycemic episodes (<40 mg/dL) in the human insulin group.26 Hypoglycemic events have been noted to be higher in patients who adhere to a human insulin regimen. Therefore, insulin analogues are preferred to avoid the sequel linked to hypoglycemic events. The authors acknowledge that wide variability exists with respect diabetes management 8
ACCEPTED MANUSCRIPT during the hospital stay. Thus, if the clinician devises an insulin-based protocol that effectively maintains blood glucose within a normal range, then it is appropriate. 3. Post-surgery management
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3.1 Preface to postoperative care
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After metabolic surgery, insulin sensitivity and secretion are improved and blood glucose
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levels are substantially diminished even before drastic weight loss.27 There is data demonstrating that insulin sensitivity and glycaemia improve equally in RYGB and sleeve gastrectomy13, 28, 29;
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thus, the implications for insulin dosing post-surgery (i.e., the extent of dose reduction) may not
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be disparate for the two procedures. However, the research is contentious as some evidence suggests slight superiority of RYGB in the short-term, but with equivalency being observed
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years later.27, 29, 30 Also, satiety is achieved more readily while hunger is reduced; there is a
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reduced drive to eat calorically dense foods.31 As a consequent, daily caloric intake is diminished
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to around 1000 kcal three months after surgery with gradual increases thereafter.32, 33 Subsequently, the specific antidiabetic regimen that is instituted is influenced by the
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patient’s glycemic status and the specific time point after surgery. Further, while incidence may plateau thereafter, the clinician should bear in mind that there is a rise in the incidence of
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hypoglycemia one year after RYGB relative to baseline.34 The authors noted that a lower age, greater weight loss, and more substantial improvements in beta-cell function predicted hypoglycemic events.34 After the initial sharp decline in blood glucose levels, the number of antidiabetic agents and the dose will be reduced acutely post-surgery. Thereafter, as weight loss progresses and glycated hemoglobin is reduced, further changes will be required. Certainly, the diabetic regimen is labile: it will progress from reinstitution acutely after surgery to withdrawal
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ACCEPTED MANUSCRIPT (i.e., as blood sugar improves) to reincorporation as disease state progresses. To guide diabetes management, an HbA1c will need to be conducted three months post-surgery and intermittently thereafter to delineate the extent of diabetes improvement. As per the ADA, although the target glucose range may be reduced or increased depending on the patient’s state (i.e., acute diabetes
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onset vs. poor diabetes control), a general goal is to attain an HbA1c <7%.35
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3.2 Insulin management and diabetic ketoacidosis after metabolic surgery
In the inpatient setting acutely post-surgery, the patient can be managed with a basal-
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bolus plus corrective insulin regimen. In patient’s that either adhered to a sliding scale (irrespective of insulin therapy status preoperatively) or a SSI and long-acting insulin regimen in
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insulin dependent patient’s, inpatient diabetes control was attained sparingly; principally, 36.3
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and 48.4% of RYGB and sleeve gastrectomy patients, respectively, demonstrated control of their
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blood glucose (defined as <180 mg/dL).36 Implying that a more intensive regimen was needed; therefore, adherence to a basal-bolus or an insulin infusion regimen as needed may be pertinent.
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Caution is advised with respect to type I diabetes (TID) patients after metabolic surgery,
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as drastic reductions in insulin dose may precipitate diabetic ketoacidosis (DKA). For instance, in a small retrospective analysis (case study), DKA was prominent (n=12) in the early
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postoperative time interval (days 0-61; median=12th day).37 Notwithstanding that non-DKA prone individuals were not included in the analysis, one predictive factor may be poor glycemic management in the preoperative period (median HbA1c was 9.3%). Nonspecific symptoms of DKA included abdominal pain, nausea, and vomiting.37 One review corroborated the results of the aforementioned retrospective study. Although the investigators did not pool the DKA frequency, DKA was shown to occur in a review of several case studies (n=107).38 What precipitated DKA was not discussed. Interestingly, even though decrements in HbA1c are 10
ACCEPTED MANUSCRIPT generally not as pronounced in patients with TID (8.3% to 7.6% vs. 8.0% to 5.9% in patients with T2D),39 postoperative insulin dose was reduced by a similar amount: a one-half reduction in most of the included trials.38 Another retrospective study verified the nearly on-half reduction in insulin dose at 6 and 12 months.39 The authors also expressed concern over the increase in
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hypoglycemia at six months post-op.39 Additional research is needed in regards to TID and
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metabolic surgery.
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If the T2D patient requires insulin after discharge, the dose, as demonstrated in the
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retrospective analysis in patients with TID, will have to be reduced. Empirical evidence indicates that among insulin dependent T2D patients, 93% of RYGB and 82% of sleeve gastrectomy
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patients reduced their long-acting insulin dose by greater than 50%, while 90.6% and 100% reduced their short-acting insulin regimen by > 50%, respectively; specifically, the average dose
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for long-acting and short-acting insulin was 10.4 and 1.7 units on discharge.36 At one year, there
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was a further reduction in insulin use; long-acting and short-acting insulin dose was 3.7 (9% of
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patients) and 1.7 units (8.4% of patients), respectively.36 Schauer et al. substantiated the results by noting that 4 and 8% of RYGB and sleeve gastrectomy patients were insulin dependent at 12
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months, respectively; at three years, the results were essentially identical, while there was a
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marginal increase to 12 and 11% at five years, respectively.29, 30, 40 Therefore, the insulin dose will need to be titrated downwards for at least up to 12 months post-surgery with a significant reduction occurring during the first month.41 The data at three and five years affirms the significant durability and efficacy of the two surgery subtypes in maintaining adequate glucose control (HbA1c ~ 7.4%) without the need for insulin therapy. Consequently, for patients receiving < 30 units of basal insulin before surgery, the dose can be withdrawn, but short-acting insulin may be used to manage postprandial glucose levels.8 11
ACCEPTED MANUSCRIPT In patients using > 30 units of basal insulin preoperatively, doses were attenuated by 50-80%.8 However, recommending and applying a one-size-fits-all insulin prescription is not feasible given the wide array of clinical presentations. Thus, recommendations should viewed as a template and not as rigid prescription for each patient. There will need to be an appropriate
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follow-up schedule in place to monitor the effectiveness of an anti-hyperglycemic regimen.
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3.3 Oral therapy
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associated fall and fracture risk with insulin therapy.42, 43
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Moreover, due to hypoglycemic events, it is important that the physician be cognizant of the
Beyond the observation that RYGB (relative to sleeve gastrectomy) patients may achieve
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T2D remission without the need for concurrent pharmacotherapy,30 studies investigating the
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effects of medicinal products after bariatric surgery are scarce. Given that an individualized
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approach will be required for each patient and be affected by the underlying surgery type, the purpose is not to advocate for a specific pharmacological regimen after metabolic surgery.
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Furthermore, a holistic review of all the potential pharmacological aids and their side effects is
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beyond the scope of the review. In general, an oral pharmacotherapy regimen that facilitates weight loss and euglycemia, while also conferring a low hypoglycemic risk is optimal.
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There are two distinct and relevant time points after metabolic surgery: acutely postsurgery and long-term after surgery. In the acute phase and upon discharge, the recommendation is that metformin, unless contraindicated, can be reinstituted as a stand-alone therapy when HbA1c is <9%15, 35; the dose will depend on the extent of glucose control and, if any, the associated side effects. The clinician may consider an additional agent if the patient is still refractory to treatment (e.g., HbA1c is 8.5%). Also, when HbA1c is >9%, a second agent can be coupled with metformin that facilitates weight loss and/or cardiovascular risk reduction in 12
ACCEPTED MANUSCRIPT selected at-risk individuals35; the agent may need to have neutral or positive effects on bone mineral density and fall risk given that, after metabolic surgery, fracture risk and BMD may be exacerbated.44-46 Consequently, prescribing thiazolidinediones are not recommended because of their negative effects on BMD.47, 48 In addition, notwithstanding the possible neutral effects on
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bone,49, 50 prescription of long-acting SU are discouraged15; the short-acting variants may be
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has generally been noted to exert positive effects on bone.51
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more suitable due to the purported lower hypoglycemic risk.9 It is worth noting that metformin
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Ultimately, as disease state progresses and weight regain becomes more prominent in a small segment of the population, the long-term approach shifts to coupling metformin with a
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pharmacological agent that has more pleiotropic effects: cardiovascular risk reduction, weight
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loss, and improved renal outcomes. As a second-tier form of therapy, there are three agents that fulfill the aforesaid criteria and may have neutral or beneficial effects on bone: the sodium-
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glucose cotransporter-2 (SGL2) inhibitors canagliflozin (neutral) and empagliflozin (neutral) and
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the glucagon-like peptide 1 (GLP-1) analogue liraglutide (beneficial).52-55
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Indeed, long-term randomized controlled trials have demonstrated improved cardiovascular and renal outcomes and reductions in all-cause mortality in the case of
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empagliflozin.56-58 The beneficial outcomes may signify a class effect and be mediated by the aggregate effect on a myriad of parameters: improvements in blood pressure, weight (~ 3 kg), lipids, and blood glucose levels. Moreover, although other medications likely exert a similar effect,59, 60 liraglutide or canagliflozin may, at the very least, stagnate the perpetual deterioration in B-cell function by attenuating the effects of glucotoxicity.59, 61, 62 However, amelioration of Bcell function may be more pronounced with liraglutide relative to insulin or exenatide.61, 62
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ACCEPTED MANUSCRIPT Possibly inferring that liraglutide improved the purported irreversible modulator of B-cell function: B-cell preservation.61 In addition, both classes of medication confer a low hypoglycemic risk. While canagliflozin is well-known to exhibit a low hypoglycemic profile,63 for liraglutide, the
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LEADER and other investigators observed a lower hypoglycemic incidence relative to placebo
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or glimepiride.57, 64 Canagliflozin’s effects are independent of insulin secretion given that it
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facilitates glucose excretion via the kidneys; the threshold for urinary glucose excretion is
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diminished to a safe range that overlies the level typified by hypoglycemia.63 However, the downside of GLP-1 analogues and SGL2 inhibitors are their possible side
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effects. For canagliflozin, the primary side effects include increased urination and thirst,
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dehydration, urinary tract infections, and genital yeast infections.63 The latter two side effects are
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more prevalent in women.63 It is unknown if side effect frequency is increased in patients who have underwent metabolic surgery. For instance, given the already exaggerated incretin response
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post-surgery, it is to be elucidated if a GLP-1 analogues may further compound hypoglycemic risk or gastrointestinal side effects. However, with respect to liraglutide, if gastrointestinal side
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effects do occur, their frequency may diminish with time.62 In addition, relative to short-acting
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variants, long-acting GLP-1 analogues may be more appropriate for patients who underwent metabolic surgery because of the improved outcomes and the diminished side effect frequency.62 While both treatments groups had similar weight loss outcomes (-3.24 [liraglutide] vs. 2.87 kg [exenatide]), HbA1c decreased more significantly (1.12% versus 0.79%) and side effects (nausea and hypoglycemia) were less common in the liraglutide group.62 Albeit retrospective in design, one trial, which is discussed in the ensuing paragraph, has shown promising results with liraglutide treatment in patients who have underwent metabolic surgery. 14
ACCEPTED MANUSCRIPT Interestingly, in addition to fostering weight loss,65 liraglutide was shown to be well tolerated by post-metabolic surgery patients.66 Specifically, in a miniscule heterogeneous sample (n=15) that mainly comprised of RYGB patients (53%), hypoglycemia occurred in 6.7% of the subjects; also, the prevalence of nausea and vomiting was 35.8% and 21.1% at three months,
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respectively.66 Importantly, at baseline, the proportion of patients with an HbA1c of <7% was
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66.7% which improved to 81.8% after treatment with liraglutide. It would be interesting if the
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results can be corroborated in additional studies and whether they can be extrapolated to other
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pharmacological classes such as SGL2 inhibitors.
Such agents that confer a myriad of positive effects may be well suited for patients who
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have underwent metabolic surgery. Principally, with metabolic surgery, not only can patients
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reduce their number of comorbidities, but they can possibly further sustain the positive outcomes with the additive effects of SGL2 or GLP-1 on cardiovascular risk and weight loss. Therefore,
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some have advocated that the concomitant effects of metabolic surgery and a SGL2 inhibitor or a
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long-acting GLP-1 analogue may be highly therapeutic for patients with T2D; given that the positive effects of metabolic surgery subside with time, an SGL2 inhibitor or GLP-1 analogue
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may extend the durability of the positive outcomes by fostering weight loss and cardiovascular
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risk reduction (etc.). As opposed to the traditional emphasis on using metformin as the primary monotherapy, a regimen that couples metabolic surgery with either of the aforementioned classes of medication (SGL2 or GLP-1) represents a contemporary view on diabetes management. Indubitably, other SGL2 inhibitors, long-acting GLP-1 analogues, and dipeptidyl peptidase-4 inhibitors warrant consideration. Additional research will be required to justify their prescription over other pharmacological aids.
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Figure 1. Medical management of diabetes in metabolic surgery patients Preoperative and Postoperative Recommendations Preoperative Oral
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Insulin
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-
Oral
Postoperative
- Reincorporate metformin (A1c <9%) - Add incretin, DPP-4, or glucose inhibitor (A1c >9%) - Subject to inquiry: introduce incretin analogued or glucose inhibitor as stand-alone therapy after discharge (A1c <9%)
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- Withdraw long-acting - Decrease dose by Sulfonylurea about 50%a - Maintain or reduce - Nonhuman insulin glucose inhibitor, is recommended c metformin, incretin, or DPP-4 inhibitor dose
Insulin
- Decrease overall dose by about 50%b - Human insulin is not recommended - Dose may have to be titrated down for up to 12 months - Premixed insulin may heighten hypoglycemic risk
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Dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitors). (a) When instituting a very low calorie diet at least two weeks prior to surgery; (b) insulin dose is relative to preoperative dose and before a very low calorie diet. (c) Due to associated hypoglycemic risk, human insulin is not advised. (d) Long-acting incretin analogue is suggested.
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Table 1. Additional considerations and recommendations Preoperatively 1. Try to implement an exercise regimen with a very low calorie diet to offset decreases in lean muscle mass. Note that total caloric intake may need to be increased slightly as a result. 2. Maintain some communication with the patient to help reduce the incidence of hypoglycemia and to facilitate adherence. 3. If the patient is more poorly controlled, then they will likely necessitate a more intensive insulin regimen during the inpatient stay. Further, the implications for medication withdrawal and/or reincorporation, in the postoperative period, will be different than for those who are more optimally controlled. Thus, preparation can begin during the preoperative period. Perioperative and inpatient setting 1. Implement an insulin protocol that minimizes the risk of hypoglycemia and hyperglycemia. 2. Depending on the patient’s state, a continuous infusion or rapid acting insulin regimen are recommended during perioperative period.18 3. Monitor blood glucose levels diligently. 4. Prepare for and refine patient-specific discharge guidelines. Postoperatively 1. Have the patient meet with a multidisciplinary team if possible. For instance, appropriate follow-up with the surgeon, endocrinologist, dietician, and if possible a trained fitness professional is recommended. 2. Exercise and dietary adherence is advised for more favorable and durable outcomes.
3.4 Pharmacokinetics and pharmacodynamics after metabolic surgery
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Given the gastrointestinal adaptations that ensue, pharmacokinetics and/or pharmacodynamics may be influenced. For example, metformin’s bioavailability was paradoxically shown to be improved in subjects who underwent RYGB > 3 months prior to commencing the study.67 Another study also demonstrated that RYGB subjects who had surgery greater than one year ago had an improved pharmacokinetic profile; time from ingestion to maximal concentration was truncated for each of the constituent substances in an ingested cocktail: caffeine, tolbutamide, omeprazole, and midazolam.68 17
ACCEPTED MANUSCRIPT Whether there is an improvement or a decrement in gastric emptying is subject to further inquiry,69 but in either case metabolic surgery likely has an effect on drug pharmacokinetics; moreover, intestinal transit time or intestinal adaptations may elicit an alteration in drug pharmacokinetics/dynamics.67, 68 The relative time point (i.e., acutely or long-term after surgery)
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when a pharmacokinetic/pharmacodynamic study is undertaken may also be pertinent as
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intestinal adaptations may not manifest shortly after surgery.68 Further, gastric pH may also
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affect drug digestion given that pH is increased in RYGB subjects.70 The study of the effects of metabolic surgery on pharmacokinetics/dynamics is in its infancy and its possible effects are
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4. Conclusion and future considerations
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strictly conjecture at this time given the lack of evidence.
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First and foremost, we do not wish to imply that all patients who undergo metabolic
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surgery experience suboptimal results in the long-term. Indeed, this is not true as only a small portion of the population may have diabetes relapse and experience weight regain. We cannot
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emphasize enough that even if the patient experiences weight regain, the positive effects are still
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drastic in comparison to baseline and in relation to other forms of therapy. When guiding care, the clinician should be cognizant of the effects of varying metabolic
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surgery procedures. For example, without the concomitant need for oral therapy, RYGB has substantial effects on diabetes remission; thus, patients undergoing RYGB may require their pharmacotherapy regimen be fine-tuned more substantially. Along the same lines, diabetes history and extent of control have implications on inpatient and postoperative care. Patients who are poorly controlled in the preoperative period may require more intensive insulin dosing regimens perioperatively and predict lower rates of diabetes remission postoperatively. Therefore, they are less likely to be weaned off their oral therapy. 18
ACCEPTED MANUSCRIPT As pragmatic advice, patients should be screened appropriately and educated on the benefits and risks of metabolic surgery. They must have realistic expectations before proceeding with surgery. Even though metabolic surgery fosters drastic weight loss outcomes, a majority of the patients will still be obese.
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A large portion of the cited evidence comes from ancillary fields and, therefore, is not necessarily metabolic surgery specific. There are a myriad of areas within the umbrella of
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metabolic surgery care that require further research: pharmacodynamics/pharmacokinetics after
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surgery, inpatient and perioperative glucose management, and pre and postoperative insulin dosing requirements. In addition, delineating an optimal oral therapy regimen after metabolic
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surgery requires further study.
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Acknowledgements: N/A
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Funding source: N/A
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Conflict of interest: The authors report no conflicts of interest.
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ACCEPTED MANUSCRIPT References
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36. Zaman J, Shah N, Leverson G, Greenberg J, Funk L. The effects of optimal perioperative glucose control on morbidly obese patients undergoing bariatric surgery. Surgical Endoscopy. 2017;31(3): 14071413. 37. Aminian A, Kashyap S, Burguera B, et al. Incidence and clinical reatures of diabetic ketoacidosis after bariatric and metabolic surgery. Diabetes Care. 2016;39(4): e50-e53. 38. Kirwan J, Aminian A, Kashyap S, Burguera B, Brethauer S, Schauer P. Bariatric surgery in obese patients with type 1 diabetes. Diabetes Care. 2016;39(6): 941-948. 39. Faucher P, Poitou C, Carette C, et al. Bariatric surgery in obese patients with type 1 diabetes: effects on weight loss and metabolic control. Obesity Surgery. 2016;26(10): 2370-2378. 40. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. New England Journal of Medicine. 2014;370(21): 2002-2013. 41. Tritsch A, Bland C, Hatzigeorgiou C, Sweeney L, Phillips M. A retrospective review of the medical management of hypertension and diabetes mellitus following sleeve gastrectomy. Obesity Surgery. 2015;25(4): 642-647. 42. Wallander M, Axelsson K, Nilsson A, Lundh D, Lorentzon M. Type 2 diabetes and risk of hip fractures and non-skeletal fall injuries in the elderly: A study rrom the rractures and fall injuries in the elderly cohort (FRAILCO). Journal of Bone and Mineral Research. 2017;32(3): 449-460. 43. Schwartz A, Hillier T, Sellmeyer D, et al. Older women with diabetes have a higher risk of falls: a prospective study. Daibetes Care. 2002;25(10): 1749-1754. 44. Yu E, Bouxsein M, Putman M, et al. Two-year changes in bone density after Roux-en-Y gastric bypass surgery. Journal of Clinical Endocrinology and Metabolism. 2015;100(4): 1452-1459. 45. Shanbhogue V, Støving R, Frederiksen K, et al. Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: a two-year longitudinal study. European Journal of Endocrinology. 2017;176(6): 685-693. 46. Yu E, Lee M, Landon J, Lindeman K, Kim S. Fracture risk after bariatric surgery: Roux-en-Y gastric bypass versus adjustable gastric banding. Journal of Bone and Mineral Research. 2017;32(6): 1229-1236. 47. Ali A, Weinstein R, Stewart S, Parfitt A, Manolagas S, Jilka R. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005;146(3): 12261235. 48. Lecka-Czernik B, Ackert-Bicknell C, Adamo M, et al. Activation of peroxisome proliferatoractivated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Bone. 2007;148(2): 903-911. 49. Zinman B, Haffner S, Herman W, et al. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism. 2010;95(1): 134-142. 50. Vianna A, de Lacerda C, Pechmann L, et al. Vildagliptin has the same safety profile as a sulfonylurea on bone metabolism and bone mineral density in post-menopausal women with type 2 diabetes: a randomized controlled trial. Diabetology & Metabolic Syndrome. 2017;9. 51. Marycz K, Tomaszewski K, Kornicka K, et al. Metformin decreases reactive oxygen species, enhances osteogenic properties of adipose-derived multipotent mesenchymal stem cells in vitro, and increases bone density In vivo. Oxidative Medicine and Cellular Longevity. 2016;2016. 52. Watts N, Bilezikian J, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism. 2016;101(1): 157-166. 53. Henriksen D, Alexandersen P, Hartmann B, et al. Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone. 2009;45(5): 833-842.
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