- Email: [email protected]
Integrating medical and surgical therapies to optimize the outcomes of type 2 diabetes
Surgery for Obesity and Related Diseases ] (2016) 00–00
Video case report
Integrating medical and surgical therapies to optimize the outcomes of type 2 diabetes Giovanni Ceccarini, M.D.a, Anna Maria Ciccarone, M.D.b, Ferruccio Santini, M.D.a, Stefano Del Prato, M.D.b,* a
Endocrine Section, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Diabetes Section, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Received December 1, 2015; accepted January 29, 2016
b
Abstract
Modern treatment of type 2 diabetes must rely on therapy individualization. Morbid obesity confers an independent excess of risk to diabetes. In these individuals metabolic surgery is an opportunity the physician should consider, especially at the time of the diabetes diagnosis, because of its efficacy and long-term effects. In addition to the possible remission of diabetes, bariatric surgery is also associated with reduced risk of micro- and macrovascular complications. A multidisciplinary team approach is necessary to maximize the beneficial effects and minimize the adverse events of metabolic surgery and to ensure proper follow-up based on the residual possibility of developing complications. In this regard, a consensus on definition of remission must be reached to define the residual risk after antidiabetic drug withdrawal. Finally, randomized clinical trials are deemed necessary to establish the risk-to-benefit profile of glucose-lowering agents for those patients who have remained diabetic or experience a disease relapse. (Surg Obes Relat Dis 2016;]:00–00.) r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Glucose control remains the primary objective in the treatment of patients with type 2 diabetes (T2D) to reduce the burden of long-term complications although there is an uncertain benefit for strict glycemic control on cardiovascular outcomes. Furthermore, possible harm may be caused when pursuing an aggressive therapeutic target in older patients with a long history of the disease [1]. Both clinical and biochemical factors should be taken into account when deciding how intensive glucose lowering should be accomplished and which pharmacologic approach to use. In other words, in evaluating the best therapeutic strategy, a personalized approach is necessary and recommended by most recent guidelines [2]. Glycemic target and treatment selection should be based on the individual patient’s *
Correspondence to: Stefano Del Prato, M.D., Section of Metabolic Diseases and Diabetes Via Paradisa, 2, 56124 Pisa, Italy. E-mail: [email protected]
characteristics including age, life expectancy, co-morbidities, and many other factors. Drug features such as efficacy, costs, side effects, dosing schedule, and effect on weight are also part of the decision-making algorithm [2]. In a diabetic population where obesity is quite prevalent, weight plays an important role in treatment strategy definition. Thus, overweight and mildly obese patients may benefit from treatment with metformin, which remains the first line treatment in all patients with T2D. In obese patients, treatment intensification will require add-on to metformin on drugs with neutral effects on weight (i.e., dipeptidyl peptidase-4 inhibitors) or, even better, favoring weight loss (i.e., glucagon-like peptide-1 [GLP-1] receptor agonists [GLP-1 RAs]) or sodium-glucose cotransporter 2 inhibitors (SGLT2-I). Body mass index (BMI) 435 kg/m2 brings the highest lifetime risk for diabetes in the United States [3]. In these individuals metabolic surgery is an opportunity the physician should consider (Fig 1). Under the name
http://dx.doi.org/10.1016/j.soard.2016.01.035 1550-7289/r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
2
G. Ceccarini et al. / Surgery for Obesity and Related Diseases ] (2016) 00–00
Fig. 1. Treatment strategies in patients affected by type 2 diabetes based on BMI categories. SUs ¼ sulfonylureas; DPP4-I ¼ dipeptidyl peptidase-4 inhibitors; GPL-1 RAs ¼ GLP-1 receptor agonists; SGTL2-I ¼ sodiumglucose cotransporter 2 inhibitors. (Reprinted with permission)
“metabolic surgery” falls all surgical procedures and devices aimed at modifying the anatomy of the gastrointestinal tract to achieve weight loss and metabolic benefits, with the latter being, to some extent, independent of weight reduction. Almost 60 years after the initial description of the amelioration of diabetes after subtotal gastrectomy, recommendations have been released for the adoption of bariatric/metabolic surgery as antidiabetes intervention [4–6]. At the recent 2nd Diabetes Surgery Summit, experts have concurred that the “multimodal algorithms for treating T2D should include specific scenarios in which diabetes surgery is considered a treatment option in addition to lifestyle, nutritional, and/or pharmacologic approaches”[7]. Metabolic surgery is associated with high rates of shortterm (o2 years) remission of diabetes, which can vary between 55% and 94% based upon the type of surgery and definition of remission [8,9]. Similar results have been confirmed in randomized, controlled trials of surgically treated patients compared with standard lifestyle and medical therapy [10–12]. Rates of remission tend to level off to 30% in longer follow-up (15 years) as reported in the Swedish Obesity Study [13]. Of relevance, over the 15 years of observation of the Swedish cohort a lower rate of long-term micro- and macrovascular complications were recorded compared with a control group of obese diabetic patients managed by conventional nonsurgical therapies [12]. Moreover, the rates of remission of hypertension and dyslipidemia at 1 year were 440%, and left ventricular hypertrophy was reduced in diabetic patients just 1 year after Roux-en-Y gastric bypass (RYGB) [14,15]. Also, bariatric surgery improved quality of life along with improvement of obesity co-morbidities [16]. Maximizing the long-term beneficial effect of metabolic surgery Identification of those patients with the greatest chance to benefit from metabolic surgery is of great importance given
the individual and societal burden of expensive procedures such as surgical intervention. A limited number of studies are available to fully assess the effect of surgery in diabetic patients with lower BMI (3035 kg/m2), although their results suggest similar percentages of short-term disease remission and overall reduction of need of antidiabetic medications [17]. A short duration of diabetes is associated with higher remission rates both in the short and the long term, while BMI at surgery does not influence the rate of remission or the effect on diabetes complications [13]. The degree of involvement of underlying mechanisms responsible for glucose intolerance is of great relevance. Interestingly enough, the best predictor of diabetes remission is the degree of beta-cell glucose sensitivity before surgery, while insulin sensitivity improves along with weight loss. The higher the beta-cell glucose sensitivity, the likelier the remission of diabetes [18]. These observations suggest the need to consider metabolic surgery at an earlier stage of the disease [19]. The type of bariatric procedure is critical for the remission rate of T2D. The meta-analysis from Buchwald et al. indicates an average resolution of diabetes in 56% of gastric bandings, 79% of gastroplasties, 80% of gastric bypasses, and 95% of biliopancreatic diversions [9]. More recently, positive results have been reported with alternative techniques such as the endoluminal barrier approach [20]. This brief outline of the many elements that may concur in determining the outcome of the metabolic surgery clearly indicates the need of careful assessment of the candidate patient. Such an approach does require a multidisciplinary approach, where specific expertise can add in exploiting the advantage of metabolic surgery. For instance, obese individuals who underwent RYGB only had a lower weight loss at 6 and 12 months after surgery compared with those undergoing the surgical procedure as part of a multidisciplinary approach [21]. Surgical and medical therapy could act in synergy to achieve results surgery alone may not provide. For instance, animal studies have shown that treating animals with gastric banding with a GLP-1 receptor agonist can lead to lower food intake, greater weight loss, and greater reduction of fat mass while preserving lean body mass [22]. The experiment, therefore, provides the basis of a combined treatment when other more effective forms of surgery may not be indicated. The presence of a multidisciplinary team may also be of importance in reducing the risk of metabolic surgery either by reducing concomitant risk conditions or via risk grading. For instance, recognition and presurgery treatment of patients with metabolic syndrome (defined as the concomitance of hypertension, diabetes, and dyslipidemia at presentation of surgery) may be necessary since an increased risk of severe complications (2.4% versus 1%) and death (0.3% versus .1%) after the surgical procedure has been reported in these individuals [14].
Medical and Surgical Therapy Integration for T2D Outcomes / Surgery for Obesity and Related Diseases ] (2016) 00–00
Defining remission of diabetes after metabolic surgery Up to 90% of patients discontinue hypoglycemic treatment after metabolic surgery [15]. However, the rate of remission can be affected by multiple factors including how remission is defined. For instance, Blackstone et al. have reported that remission of diabetes 14 months after surgery can vary from 40% to 60% according to the criteria of definition of remission [23]. The issue is not of a simple solution and is a matter of discussion not only in the medical community, but also, unexpectedly, in veterinary medicine as well [24]. So far the most commonly used definition for remission is the one proposed by the Expert Committee of the American Diabetes Association (ADA) [25], which has defined complete remission when normal measures of glucose metabolism (fasting plasma glucose o100 mg/dL and HbA1c o6%) are obtained in the absence of medications for at least 1 year; prolonged remission is achieved when the time elapsed is longer than 5 years. Partial remission should be referred to those individuals reaching levels of hyperglycemia, which are above the normal range (fasting plasma glucose 100125 mg/dL and HbA1c o6.5%) and below diagnostic values for diabetes. Such definitions are not a categorization exercise; rather, it marks the condition at which an individual is not just taking glucose-lowering agents, but, more importantly, it establishes the extent that person is free of risk of developing diabetic complications. Identifying individuals with residual mild alterations of glucose homeostasis after bariatric surgery may pinpoint patients still retaining significant risk of microvessel complications. In the Diabetes Prevention Program, diabetic retinopathy was documented in 7.9% of high-risk nondiabetic patients compared with the 12.6% of patients with newly diagnosed diabetes [26]. We have found that patients with prediabetes are characterized by a worse cardiovascular risk profile as indicated by reduced flow mediated dilation, increased intimamedia thickness, increased pressure wave velocity, inflammatory state, and reduced number of circulating endothelial progenitor cells [27]. We believe it is appropriate that guidelines recommend monitoring diabetic patients after surgery as part of the standard care of a diabetic person [7,28]. In particular, for those who have reached a stable normalization of glycemia for no less than 6 months, the follow-up should parallel that applied to prediabetic patients due to the risk of complications and disease relapse. Even when disease remission is achieved, monitoring of diabetes complications should continue at least during the first 5 years after surgery. The frequency of the follow-up visits should be based on the severity of existing complications, with the interval being longer in the absence of complications and the shortest in the case of severe complications. After a 5-year remission, the monitoring of specific complications may be discontinued only if there is no history of diabetic complications
3
[7,25]. Diabetic complications, moreover, may worsen regardless of glucose level, being influenced by other factors such as anemia, low vitamin B levels, and other surgery-related nutritional deficits [29]. A list of such nutritional concerns and relative treatments has been carefully detailed in the Guidelines of the Endocrine Society [28]. How to treat nonremitters and recurrences of diabetes? In spite of the high rate of remission, diabetic hyperglycemia may not resolve in a sizable percentage of patients, with another significant proportion relapsing over the time, raising the issue of what is the preferred antihyperglycemic treatment in patients in whom the gut anatomy and physiology has been significantly altered. The rate of recurrence of diabetes, as mentioned, is affected by a number of factors, including the type of surgery and initial and postsurgery change of insulin sensitivity and beta-cell function, although the latter seems to be a better predictor of postsurgery glucose outcomes [18,30]. The extent to which assessment of residual beta-cell function on the basis of basal C-peptide can support treatment decision has not been widely investigated, but this approach may suffer of all the limitations already pointed out with respect to the usual treatment of T2D. No official guideline has declared a formal position with respect to drug selection for patients with persistent diabetes or diabetes recurrence. Khanna and Kashyap have recently published a proposal for a treatment flowchart [31]. According to their view, diet counseling and physical activity provide the usual therapeutic background. Metformin, GLP-1 RAs, and SGLT2-I are considered first-line options for patients who are still obese [31]. Metformin is deemed a rational therapeutic choice due to its ability to promote weight loss, to improve insulin sensitivity by suppressing hepatic gluconeogenesis, and to increase muscle and liver glucose uptake through AMP-activated protein kinase activation. A lower dose of metformin may be necessary since metformin bioavailability can increase by 50% after bariatric surgery [32]. Moreover, metformin often causes diarrhea as a side effect, and its use should be considered with caution after biliopancreatic diversion with or without duodenal switch. Unlike metformin, thiazolidinediones (TZD) promote weight gain and should be considered as a second-line therapy for patients who do not achieve glucose control of their residual diabetes with metformin, preferentially after sleeve gastrectomy rather than in patients with RYGB or biliopancreatic diversion [31]. For patients who are not significantly overweight, these authors suggest adopting treatments that may minimize further beta-cell failure. The proposal may, however, require a more systematic assessment of the advantages and disadvantages of the available glucose-lowering drugs in such a selected group of diabetic patients. Table 1 provides a synopsis of such features.
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G. Ceccarini et al. / Surgery for Obesity and Related Diseases ] (2016) 00–00
Table 1 Synopsis of the possible advantages and disadvantages of the antihyperglycemic agents available for the treatment of diabetes after metabolic surgery Agent
Advantages
Disadvantages
Concerns
Gastrointestinal side effects
Increased bioavailability
Sulfonylureas
↑ Hepatic 4 peripheral insulin action Modest anorectic effect Beta-cell stimulation
Beta-cell loss?
Thiazolidinediones
↑ Hepatic and peripheral insulin action
Hypoglycemia Weight gain Weight gain Bone fractures Gastrointestinal side effects
↑ GLP-1 after RYGB ↑ GLP-1 after RYGB
Genital infection (F 4 M)
Ion metabolism?
Hypoglycemia Weight gain
Cardiovascular risk?
Metformin
DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
Insulin
↓ Hypoglycemia↑ GLP-1 ↓ Hypoglycemia ↑↑ GLP-1 ↓ Hypoglycemia ↓ Weight ↓Blood pressure Cardiovascular protection Efficacious
Fluid retention
DPP-4 ¼ dipeptidyl peptidase-4; GLP-1 ¼ glucagon-like peptide-1; RYGB ¼ Roux-en-Y gastric banding; SGLT2 ¼ sodium-glucose cotransporter 2 inhibitors; F ¼ female; M ¼ male.
Khanna and Kashyap suggest considering sulfonylurea in individuals who still remain hyperglycemic after a malabsorptive surgical procedure and have no weight regain or have a BMI r27 kg/m2 [31]. Sulfonylureas, however, stimulate insulin secretion in a glucose-independent manner, increasing the risk of hypoglycemia and, therefore, potentially worsening dumping symptoms. Moreover, these molecules may not be the best option if preservation of beta-cell function is sought, and doubts have been cast about the potential activation of beta-cell apoptosis. A betacell protective effect has been claimed for TZD in vitro and in experimental animals. In line with this preclinical data, rosiglitazone has been claimed to retain, in treatment-naïve patients, a more durable effect because of its insulin sensitizing effect along with maintenance of beta-cell function [33]. However, TZD use has been associated with an increased risk of bone fracture, a condition that may be further increased in the presence of calcium and other electrolyte malabsorption. Finally, a common side effect of these compounds is fluid retention that may limit their indication in patients with class New York Heart Association II-IV, a condition common in patients with a long history of increased blood pressure as it occurs in obese patients. Dipeptidyl peptidase-4 inhibitors and GLP-1 RAs have the well-established advantage of being weight neutral and eliciting weight loss, respectively. A number of preclinical studies have provided evidence for a protective effect of beta-cell mass and restoration of beta-cell function, although demonstration of such an effect is practically nonexistent in humans. The only concern may be the gastrointestinal side effects that may be associated with the use of GLP-1 RAs. It also remains to be defined the extent to which it may sound rational using drugs that increase levels of or availability of circulating GLP-1. Since one of the principal mechanisms explaining weight loss and metabolic
control after surgery is the increase of GLP-1 circulating levels, the potential role of incretin mimetics in this setting has to be further investigated. It could be postulated, for instance, that the recurrence of diabetes after metabolic surgery is not the result of insufficient GLP-1 stimulation but rather that the incretin pathway is overridden by other dysfunctional mechanisms. Recently, great emphasis has been put on the use of SGLT2-I. These drugs act by lowering the glucose tubular threshold, resulting in glycosuria and subsequent glucose lowering regardless of direct modulation of insulin action and secretion. Because of this, the risk of hypoglycemia is low. Moreover, loss of glucose through the urine means loss of calories, hence moderate but durable weight loss [34]. Osmotic diuresis is also activated, which may reduce circulating volume and cause blood pressure reduction [34]. Even more interestingly, the recent results of the EMPA-REG OUTCOME trial have shown significant risk reduction in cardiovascular and all case mortality and risk of hospitalization for heart failure [35]. The same trial has confirmed what registration studies have shown in terms of safety profile: no risk of hypoglycemia, bone fractures, and euglycemic ketoacidosis. No difference also was found with respect to urinary tract infections, while genital infections are the most common side effect, particularly in women [35]. Whether this favorable profile may also apply in persistent or relapsing diabetes after metabolic surgery remains to be ascertained. Some questions need to be addressed. For instance, the Food and Drug Administration has recently released a warning for risk of bone fracture with canagliflozin and for euglycemic ketoacidosis [36,37]. Whether alterations of ion absorption/metabolism that may follow metabolic surgery, or impaired nutrient intake may accelerate these processes when using a SGLT2-I must be carefully considered.
Medical and Surgical Therapy Integration for T2D Outcomes / Surgery for Obesity and Related Diseases ] (2016) 00–00
In summary, a sufficiently broad glucose-lowering armamentarium is available. However, no proper study has yet been performed to determine whether the rational for treatment and the risk-to-benefit ratio derived from the population with T2D applies to the same extent in people with diabetes after metabolic surgery. Moreover, anatomic changes subsequent to metabolic surgery may alter the rate of absorption of a molecule, resulting in a shift in pharmacokinetic and pharmacodynamics parameters. Conclusion Modern treatment of T2D must rely on treatment individualization. This process should weigh all therapeutic opportunities including metabolic surgery. The latter should be considered at the time of the diabetes diagnosis in a morbidly obese individual because of its efficacy and long-term effects. A multidisciplinary team approach is necessary to maximize beneficial effects and minimize adverse events of metabolic surgery. Also, a multidisciplinary approach has to be put in place to ensure persistent effect on remitters by proper followup based on the residual risk of developing complications. To this purpose, a consensus on the definition of remission must be reached that defines residual risk after antidiabetic drug withdrawal. Finally, ad hoc studies are deemed necessary to establish proper use and risk-to-safety profile of glucoselowering agents for those patients who have remained diabetic or experience a disease relapse along with a better understanding of changes of pharmacokinetic and pharmacodynamics of oral antidiabetes drugs.
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[14]
[15]
[16]
Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.
[17]
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(EASO OMTF). Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Surg 2014;24(1):42–55. Rubino F, Nathan DM, Eckel RH, et al. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 2016. In press. Levy P, Fried M, Santini F, Finer N. The comparative effects of bariatric surgery on weight and type 2 diabetes. Obes Surg 2007;17 (9):1248–56. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009;122(3):248–56. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA 2008;299(3):316–23. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N Engl J Med 2014;370(21):2002–13. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatricmetabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 2015;386 (9997):964–73. Sjöström L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA 2014;311 (22):2297–304. Inabnet WB, Winegar DA, Sherif B, Sarr MG. Early outcomes of bariatric surgery in patients with metabolic syndrome: an analysis of the bariatric outcomes longitudinal database. J Am Coll Surg 2012;214(4):550–7. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial. Diabetes Res Clin Pract 2013;101(1):50–6. O’Brien PE, Dixon JB, Laurie C, et al. Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program: a randomized trial. Ann Intern Med 2006;144 (9):625–33. Parikh M, Chung M, Sheth S, et al. Randomized pilot trial of bariatric surgery versus intensive medical weight management on diabetes remission in type 2 diabetic patients who do NOT meet NIH criteria for surgery and the role of soluble RAGE as a novel biomarker of success. Ann Surg 2014;260(4):617–22. Nannipieri M, Mari A, Anselmino MJ, et al. The role of beta-cell function and insulin sensitivity in the remission of type 2 diabetes after gastric bypass surgery. J Clin Endocrinol Metab 2011;96 (9):E1372–9. Chen Y, Zeng G, Tan J, Tang J, Ma J, Rao B. Impact of Roux-en-Y gastric bypass surgery on prognostic factors of type 2 diabetes mellitus: meta-analysis and systematic review. Diabetes Metab Res Rev 2015;31(7):653–62. Rohde U, Hedback N, Gluud LL, Vilsboll T, Knop FK. Effect of the EndoBarrier Gastrointestinal Liner on obesity and type 2 diabetes: systematic review and meta-analysis. Diabetes Obes Metab 2016;18 (3):300–5. Patel P, Hartland A, Hollis A, et al. Tier 3 multidisciplinary medical weight management improves outcome of Roux-en-Y gastric bypass surgery. Ann R Coll Surg Engl 2015;97(3):235–7. Habegger KM, Kirchner H, Yi CX, et al. GLP-1 R agonism enhances adjustable gastric banding in diet-induced obese rats. Diabetes 2013;62(9):3261–7. Blackstone R, Bunt JC, Cortés MC, Sugerman HJ. Type 2 diabetes after gastric bypass: remission in five models using HbA1 c, fasting blood glucose, and medication status. Surg Obes Relat Dis 2012;8 (5):548–55.
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[24] Gostelow R, Forcada Y, Graves T, Church D, Niessen S. Systematic review of feline diabetic remission: separating fact from opinion. Vet J 2014;202(2):208–21. [25] Buse JB, Caprio S, Cefalu WT, et al. How do we define cure of diabetes? Diabetes Care 2009;32(11):2133–5 [26] Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med 2007;24(2):137–44. [27] Fadini GP, Pucci L, Vanacore R, et al. Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia 2007;50(10):2156–63. [28] Heber D, Greenway FL, Kaplan LM, Livingston E, Salvador J, Still C. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010;95(11):4823–43. [29] Ikramuddin S, Billington CJ, Lee WJ, et al. Roux-en-Y gastric bypass for diabetes (the Diabetes Surgery Study): 2-year outcomes of a 5year, randomised, controlled trial. Lancet Diabetes Endocrinol 2015;3 (6):413–22. [30] Brethauer SA, Aminian A, Romero-Talamás H, et al. Can diabetes be surgically cured? Long-term metabolic effects of bariatric surgery in obese patients with type 2 diabetes mellitus. Ann Surg 2013;258 (4):628–37. [31] Khanna V, Kashyap SR. Clinical management of type 2 diabetes mellitus after bariatric surgery. Curr Atheroscler Rep 2015;17(10):59.
[32] Padwal RS, Gabr RQ, Sharma AM, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care 2011;34(6):1295–300. [33] Kahn SE, Lachin JM, Zinman B, et al. Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT. Diabetes 2011;60(5):1552–60. [34] Del Prato S, Nauck M, Durán-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab 2015;17(6):581–90. [35] Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015 26;373(22):2117–28. [36] U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density [cited 2015 Nov 20]. Available from: 〈http://www.fda.gov/Drugs/DrugSafety/ ucm461449.htm〉. [37] U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood [cited 2015 Nov 20]. Available from: 〈http://www.fda.gov/Drugs/DrugSafety/ucm446845. htm〉.
Video case report
Integrating medical and surgical therapies to optimize the outcomes of type 2 diabetes Giovanni Ceccarini, M.D.a, Anna Maria Ciccarone, M.D.b, Ferruccio Santini, M.D.a, Stefano Del Prato, M.D.b,* a
Endocrine Section, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Diabetes Section, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Received December 1, 2015; accepted January 29, 2016
b
Abstract
Modern treatment of type 2 diabetes must rely on therapy individualization. Morbid obesity confers an independent excess of risk to diabetes. In these individuals metabolic surgery is an opportunity the physician should consider, especially at the time of the diabetes diagnosis, because of its efficacy and long-term effects. In addition to the possible remission of diabetes, bariatric surgery is also associated with reduced risk of micro- and macrovascular complications. A multidisciplinary team approach is necessary to maximize the beneficial effects and minimize the adverse events of metabolic surgery and to ensure proper follow-up based on the residual possibility of developing complications. In this regard, a consensus on definition of remission must be reached to define the residual risk after antidiabetic drug withdrawal. Finally, randomized clinical trials are deemed necessary to establish the risk-to-benefit profile of glucose-lowering agents for those patients who have remained diabetic or experience a disease relapse. (Surg Obes Relat Dis 2016;]:00–00.) r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Glucose control remains the primary objective in the treatment of patients with type 2 diabetes (T2D) to reduce the burden of long-term complications although there is an uncertain benefit for strict glycemic control on cardiovascular outcomes. Furthermore, possible harm may be caused when pursuing an aggressive therapeutic target in older patients with a long history of the disease [1]. Both clinical and biochemical factors should be taken into account when deciding how intensive glucose lowering should be accomplished and which pharmacologic approach to use. In other words, in evaluating the best therapeutic strategy, a personalized approach is necessary and recommended by most recent guidelines [2]. Glycemic target and treatment selection should be based on the individual patient’s *
Correspondence to: Stefano Del Prato, M.D., Section of Metabolic Diseases and Diabetes Via Paradisa, 2, 56124 Pisa, Italy. E-mail: [email protected]
characteristics including age, life expectancy, co-morbidities, and many other factors. Drug features such as efficacy, costs, side effects, dosing schedule, and effect on weight are also part of the decision-making algorithm [2]. In a diabetic population where obesity is quite prevalent, weight plays an important role in treatment strategy definition. Thus, overweight and mildly obese patients may benefit from treatment with metformin, which remains the first line treatment in all patients with T2D. In obese patients, treatment intensification will require add-on to metformin on drugs with neutral effects on weight (i.e., dipeptidyl peptidase-4 inhibitors) or, even better, favoring weight loss (i.e., glucagon-like peptide-1 [GLP-1] receptor agonists [GLP-1 RAs]) or sodium-glucose cotransporter 2 inhibitors (SGLT2-I). Body mass index (BMI) 435 kg/m2 brings the highest lifetime risk for diabetes in the United States [3]. In these individuals metabolic surgery is an opportunity the physician should consider (Fig 1). Under the name
http://dx.doi.org/10.1016/j.soard.2016.01.035 1550-7289/r 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.
2
G. Ceccarini et al. / Surgery for Obesity and Related Diseases ] (2016) 00–00
Fig. 1. Treatment strategies in patients affected by type 2 diabetes based on BMI categories. SUs ¼ sulfonylureas; DPP4-I ¼ dipeptidyl peptidase-4 inhibitors; GPL-1 RAs ¼ GLP-1 receptor agonists; SGTL2-I ¼ sodiumglucose cotransporter 2 inhibitors. (Reprinted with permission)
“metabolic surgery” falls all surgical procedures and devices aimed at modifying the anatomy of the gastrointestinal tract to achieve weight loss and metabolic benefits, with the latter being, to some extent, independent of weight reduction. Almost 60 years after the initial description of the amelioration of diabetes after subtotal gastrectomy, recommendations have been released for the adoption of bariatric/metabolic surgery as antidiabetes intervention [4–6]. At the recent 2nd Diabetes Surgery Summit, experts have concurred that the “multimodal algorithms for treating T2D should include specific scenarios in which diabetes surgery is considered a treatment option in addition to lifestyle, nutritional, and/or pharmacologic approaches”[7]. Metabolic surgery is associated with high rates of shortterm (o2 years) remission of diabetes, which can vary between 55% and 94% based upon the type of surgery and definition of remission [8,9]. Similar results have been confirmed in randomized, controlled trials of surgically treated patients compared with standard lifestyle and medical therapy [10–12]. Rates of remission tend to level off to 30% in longer follow-up (15 years) as reported in the Swedish Obesity Study [13]. Of relevance, over the 15 years of observation of the Swedish cohort a lower rate of long-term micro- and macrovascular complications were recorded compared with a control group of obese diabetic patients managed by conventional nonsurgical therapies [12]. Moreover, the rates of remission of hypertension and dyslipidemia at 1 year were 440%, and left ventricular hypertrophy was reduced in diabetic patients just 1 year after Roux-en-Y gastric bypass (RYGB) [14,15]. Also, bariatric surgery improved quality of life along with improvement of obesity co-morbidities [16]. Maximizing the long-term beneficial effect of metabolic surgery Identification of those patients with the greatest chance to benefit from metabolic surgery is of great importance given
the individual and societal burden of expensive procedures such as surgical intervention. A limited number of studies are available to fully assess the effect of surgery in diabetic patients with lower BMI (3035 kg/m2), although their results suggest similar percentages of short-term disease remission and overall reduction of need of antidiabetic medications [17]. A short duration of diabetes is associated with higher remission rates both in the short and the long term, while BMI at surgery does not influence the rate of remission or the effect on diabetes complications [13]. The degree of involvement of underlying mechanisms responsible for glucose intolerance is of great relevance. Interestingly enough, the best predictor of diabetes remission is the degree of beta-cell glucose sensitivity before surgery, while insulin sensitivity improves along with weight loss. The higher the beta-cell glucose sensitivity, the likelier the remission of diabetes [18]. These observations suggest the need to consider metabolic surgery at an earlier stage of the disease [19]. The type of bariatric procedure is critical for the remission rate of T2D. The meta-analysis from Buchwald et al. indicates an average resolution of diabetes in 56% of gastric bandings, 79% of gastroplasties, 80% of gastric bypasses, and 95% of biliopancreatic diversions [9]. More recently, positive results have been reported with alternative techniques such as the endoluminal barrier approach [20]. This brief outline of the many elements that may concur in determining the outcome of the metabolic surgery clearly indicates the need of careful assessment of the candidate patient. Such an approach does require a multidisciplinary approach, where specific expertise can add in exploiting the advantage of metabolic surgery. For instance, obese individuals who underwent RYGB only had a lower weight loss at 6 and 12 months after surgery compared with those undergoing the surgical procedure as part of a multidisciplinary approach [21]. Surgical and medical therapy could act in synergy to achieve results surgery alone may not provide. For instance, animal studies have shown that treating animals with gastric banding with a GLP-1 receptor agonist can lead to lower food intake, greater weight loss, and greater reduction of fat mass while preserving lean body mass [22]. The experiment, therefore, provides the basis of a combined treatment when other more effective forms of surgery may not be indicated. The presence of a multidisciplinary team may also be of importance in reducing the risk of metabolic surgery either by reducing concomitant risk conditions or via risk grading. For instance, recognition and presurgery treatment of patients with metabolic syndrome (defined as the concomitance of hypertension, diabetes, and dyslipidemia at presentation of surgery) may be necessary since an increased risk of severe complications (2.4% versus 1%) and death (0.3% versus .1%) after the surgical procedure has been reported in these individuals [14].
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Defining remission of diabetes after metabolic surgery Up to 90% of patients discontinue hypoglycemic treatment after metabolic surgery [15]. However, the rate of remission can be affected by multiple factors including how remission is defined. For instance, Blackstone et al. have reported that remission of diabetes 14 months after surgery can vary from 40% to 60% according to the criteria of definition of remission [23]. The issue is not of a simple solution and is a matter of discussion not only in the medical community, but also, unexpectedly, in veterinary medicine as well [24]. So far the most commonly used definition for remission is the one proposed by the Expert Committee of the American Diabetes Association (ADA) [25], which has defined complete remission when normal measures of glucose metabolism (fasting plasma glucose o100 mg/dL and HbA1c o6%) are obtained in the absence of medications for at least 1 year; prolonged remission is achieved when the time elapsed is longer than 5 years. Partial remission should be referred to those individuals reaching levels of hyperglycemia, which are above the normal range (fasting plasma glucose 100125 mg/dL and HbA1c o6.5%) and below diagnostic values for diabetes. Such definitions are not a categorization exercise; rather, it marks the condition at which an individual is not just taking glucose-lowering agents, but, more importantly, it establishes the extent that person is free of risk of developing diabetic complications. Identifying individuals with residual mild alterations of glucose homeostasis after bariatric surgery may pinpoint patients still retaining significant risk of microvessel complications. In the Diabetes Prevention Program, diabetic retinopathy was documented in 7.9% of high-risk nondiabetic patients compared with the 12.6% of patients with newly diagnosed diabetes [26]. We have found that patients with prediabetes are characterized by a worse cardiovascular risk profile as indicated by reduced flow mediated dilation, increased intimamedia thickness, increased pressure wave velocity, inflammatory state, and reduced number of circulating endothelial progenitor cells [27]. We believe it is appropriate that guidelines recommend monitoring diabetic patients after surgery as part of the standard care of a diabetic person [7,28]. In particular, for those who have reached a stable normalization of glycemia for no less than 6 months, the follow-up should parallel that applied to prediabetic patients due to the risk of complications and disease relapse. Even when disease remission is achieved, monitoring of diabetes complications should continue at least during the first 5 years after surgery. The frequency of the follow-up visits should be based on the severity of existing complications, with the interval being longer in the absence of complications and the shortest in the case of severe complications. After a 5-year remission, the monitoring of specific complications may be discontinued only if there is no history of diabetic complications
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[7,25]. Diabetic complications, moreover, may worsen regardless of glucose level, being influenced by other factors such as anemia, low vitamin B levels, and other surgery-related nutritional deficits [29]. A list of such nutritional concerns and relative treatments has been carefully detailed in the Guidelines of the Endocrine Society [28]. How to treat nonremitters and recurrences of diabetes? In spite of the high rate of remission, diabetic hyperglycemia may not resolve in a sizable percentage of patients, with another significant proportion relapsing over the time, raising the issue of what is the preferred antihyperglycemic treatment in patients in whom the gut anatomy and physiology has been significantly altered. The rate of recurrence of diabetes, as mentioned, is affected by a number of factors, including the type of surgery and initial and postsurgery change of insulin sensitivity and beta-cell function, although the latter seems to be a better predictor of postsurgery glucose outcomes [18,30]. The extent to which assessment of residual beta-cell function on the basis of basal C-peptide can support treatment decision has not been widely investigated, but this approach may suffer of all the limitations already pointed out with respect to the usual treatment of T2D. No official guideline has declared a formal position with respect to drug selection for patients with persistent diabetes or diabetes recurrence. Khanna and Kashyap have recently published a proposal for a treatment flowchart [31]. According to their view, diet counseling and physical activity provide the usual therapeutic background. Metformin, GLP-1 RAs, and SGLT2-I are considered first-line options for patients who are still obese [31]. Metformin is deemed a rational therapeutic choice due to its ability to promote weight loss, to improve insulin sensitivity by suppressing hepatic gluconeogenesis, and to increase muscle and liver glucose uptake through AMP-activated protein kinase activation. A lower dose of metformin may be necessary since metformin bioavailability can increase by 50% after bariatric surgery [32]. Moreover, metformin often causes diarrhea as a side effect, and its use should be considered with caution after biliopancreatic diversion with or without duodenal switch. Unlike metformin, thiazolidinediones (TZD) promote weight gain and should be considered as a second-line therapy for patients who do not achieve glucose control of their residual diabetes with metformin, preferentially after sleeve gastrectomy rather than in patients with RYGB or biliopancreatic diversion [31]. For patients who are not significantly overweight, these authors suggest adopting treatments that may minimize further beta-cell failure. The proposal may, however, require a more systematic assessment of the advantages and disadvantages of the available glucose-lowering drugs in such a selected group of diabetic patients. Table 1 provides a synopsis of such features.
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Table 1 Synopsis of the possible advantages and disadvantages of the antihyperglycemic agents available for the treatment of diabetes after metabolic surgery Agent
Advantages
Disadvantages
Concerns
Gastrointestinal side effects
Increased bioavailability
Sulfonylureas
↑ Hepatic 4 peripheral insulin action Modest anorectic effect Beta-cell stimulation
Beta-cell loss?
Thiazolidinediones
↑ Hepatic and peripheral insulin action
Hypoglycemia Weight gain Weight gain Bone fractures Gastrointestinal side effects
↑ GLP-1 after RYGB ↑ GLP-1 after RYGB
Genital infection (F 4 M)
Ion metabolism?
Hypoglycemia Weight gain
Cardiovascular risk?
Metformin
DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
Insulin
↓ Hypoglycemia↑ GLP-1 ↓ Hypoglycemia ↑↑ GLP-1 ↓ Hypoglycemia ↓ Weight ↓Blood pressure Cardiovascular protection Efficacious
Fluid retention
DPP-4 ¼ dipeptidyl peptidase-4; GLP-1 ¼ glucagon-like peptide-1; RYGB ¼ Roux-en-Y gastric banding; SGLT2 ¼ sodium-glucose cotransporter 2 inhibitors; F ¼ female; M ¼ male.
Khanna and Kashyap suggest considering sulfonylurea in individuals who still remain hyperglycemic after a malabsorptive surgical procedure and have no weight regain or have a BMI r27 kg/m2 [31]. Sulfonylureas, however, stimulate insulin secretion in a glucose-independent manner, increasing the risk of hypoglycemia and, therefore, potentially worsening dumping symptoms. Moreover, these molecules may not be the best option if preservation of beta-cell function is sought, and doubts have been cast about the potential activation of beta-cell apoptosis. A betacell protective effect has been claimed for TZD in vitro and in experimental animals. In line with this preclinical data, rosiglitazone has been claimed to retain, in treatment-naïve patients, a more durable effect because of its insulin sensitizing effect along with maintenance of beta-cell function [33]. However, TZD use has been associated with an increased risk of bone fracture, a condition that may be further increased in the presence of calcium and other electrolyte malabsorption. Finally, a common side effect of these compounds is fluid retention that may limit their indication in patients with class New York Heart Association II-IV, a condition common in patients with a long history of increased blood pressure as it occurs in obese patients. Dipeptidyl peptidase-4 inhibitors and GLP-1 RAs have the well-established advantage of being weight neutral and eliciting weight loss, respectively. A number of preclinical studies have provided evidence for a protective effect of beta-cell mass and restoration of beta-cell function, although demonstration of such an effect is practically nonexistent in humans. The only concern may be the gastrointestinal side effects that may be associated with the use of GLP-1 RAs. It also remains to be defined the extent to which it may sound rational using drugs that increase levels of or availability of circulating GLP-1. Since one of the principal mechanisms explaining weight loss and metabolic
control after surgery is the increase of GLP-1 circulating levels, the potential role of incretin mimetics in this setting has to be further investigated. It could be postulated, for instance, that the recurrence of diabetes after metabolic surgery is not the result of insufficient GLP-1 stimulation but rather that the incretin pathway is overridden by other dysfunctional mechanisms. Recently, great emphasis has been put on the use of SGLT2-I. These drugs act by lowering the glucose tubular threshold, resulting in glycosuria and subsequent glucose lowering regardless of direct modulation of insulin action and secretion. Because of this, the risk of hypoglycemia is low. Moreover, loss of glucose through the urine means loss of calories, hence moderate but durable weight loss [34]. Osmotic diuresis is also activated, which may reduce circulating volume and cause blood pressure reduction [34]. Even more interestingly, the recent results of the EMPA-REG OUTCOME trial have shown significant risk reduction in cardiovascular and all case mortality and risk of hospitalization for heart failure [35]. The same trial has confirmed what registration studies have shown in terms of safety profile: no risk of hypoglycemia, bone fractures, and euglycemic ketoacidosis. No difference also was found with respect to urinary tract infections, while genital infections are the most common side effect, particularly in women [35]. Whether this favorable profile may also apply in persistent or relapsing diabetes after metabolic surgery remains to be ascertained. Some questions need to be addressed. For instance, the Food and Drug Administration has recently released a warning for risk of bone fracture with canagliflozin and for euglycemic ketoacidosis [36,37]. Whether alterations of ion absorption/metabolism that may follow metabolic surgery, or impaired nutrient intake may accelerate these processes when using a SGLT2-I must be carefully considered.
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In summary, a sufficiently broad glucose-lowering armamentarium is available. However, no proper study has yet been performed to determine whether the rational for treatment and the risk-to-benefit ratio derived from the population with T2D applies to the same extent in people with diabetes after metabolic surgery. Moreover, anatomic changes subsequent to metabolic surgery may alter the rate of absorption of a molecule, resulting in a shift in pharmacokinetic and pharmacodynamics parameters. Conclusion Modern treatment of T2D must rely on treatment individualization. This process should weigh all therapeutic opportunities including metabolic surgery. The latter should be considered at the time of the diabetes diagnosis in a morbidly obese individual because of its efficacy and long-term effects. A multidisciplinary team approach is necessary to maximize beneficial effects and minimize adverse events of metabolic surgery. Also, a multidisciplinary approach has to be put in place to ensure persistent effect on remitters by proper followup based on the residual risk of developing complications. To this purpose, a consensus on the definition of remission must be reached that defines residual risk after antidiabetic drug withdrawal. Finally, ad hoc studies are deemed necessary to establish proper use and risk-to-safety profile of glucoselowering agents for those patients who have remained diabetic or experience a disease relapse along with a better understanding of changes of pharmacokinetic and pharmacodynamics of oral antidiabetes drugs.
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.
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