Type 2 diabetes mellitus current therapies and the emergence of surgical options

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1 Type 2 diabetes mellitus current therapies and the emergence of surgical options Harold E. Lebovitz Abstract Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modification. The development of new antidiabetic agents, such as insulin analogs and incretin-based therapies, has led to treatment strategies that enable many patients with T2DM to achieve target HbA 1c levels ( 7.0%). However, many factors including those related to the patient or the health-care provider, drug inadequacies and adverse effects can interfere with the ability of some patients to reach metabolic targets. Clinical data from the USA indicate that HbA 1c concentration, blood pressure and serum levels of lipids in patients with T2DM are progressively decreasing toward the target goals set by the American Diabetes Association. These improvements in metabolic regulation have led to a 30 40% decrease in reported microvascular and macrovascular complications of diabetes mellitus in the USA. Gastric bypass surgery in morbidly obese individuals with T2DM leads to remission of the diabetes mellitus in the majority of patients and improvement in the rest. A major contributor to this improvement is an alteration in gastrointestinal hormone secretions. Interventional surgery might, therefore, be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m²) patients with T2DM who do not respond to medical therapy. Lebovitz, H. E. Nat. Rev. Endocrinol. advance online publication 8 February 2011; doi: /nrendo reviews Introduction During the past decade, improved understanding of the role of adipose tissue, the brain and the gastrointestinal tract in the pathophysiology of type 2 diabetes mellitus (t2dm) has resulted in the development of many new classes of antidiabetic agents, 1 which has led to revolutionary changes in the treatment of patients with t2dm. the results of clinical trials have provided insights into how to integrate these treatments to improve clinical outcomes. in addition, the surgical treatment of morbidly obese patients over the past decade indicates that gastric surgery could be another treatment modality for patients with t2dm. 2,3 as might have been expected, extensive weight loss in markedly obese individuals (BMi 35 kg/m 2 ) with t2dm improves hyperglycemia and obesity-related cardiovascular disease risk factors. 2,3 surprisingly, some bariatric surgical procedures, such as roux-en-y gastric bypass (rygb) and biliopancreatic diversion, caused striking improvements in hyperglycemia in severely obese patients with t2dm within days or weeks of the procedure and before the patients had experienced any notable weight loss. 2,3 these two bariatric surgical procedures divert nutrients directly into the intestines. this diversion changes the gastrointestinal exposure to nutrient loads, which results in radical alterations in gastrointestinal hormone secretory patterns. 4,5 the differing competing interests The author declares associations with the following companies: Amylin, AstraZeneca, American Type Culture Collection, Biocon Pharma, Enzymotec, GlaxoSmithKline, Indigene, Intarca Pharmaceuticals, Merck, Metacure, Poxel Pharma, Sanofi Aventis. See the article online for full details of the relationships. combinations of the change in gastrointestinal hormone secretions, the reduced caloric intake and the weight loss following various bariatric surgical procedures result in dramatic improvements in diabetes regulation in severely obese individuals with t2dm. 2,3 the surgical approach is now being extended to overweight and obese (BMi <35 kg/m 2 ) patients with t2dm. this review discusses the current therapies for patients with t2dm and assesses the relative benefits and risks of surgical treatment of overweight and obese patients with t2dm in light of the latest successes and the limitations of current medical treatment. Current therapies lifestyle modification Many studies show that lifestyle modification can improve glycemic control in patients with t2dm; however, lifestyle modification alone is rarely sufficient to achieve target glycemic goals. 6,7 in most patients, lifestyle modification must be combined with pharmacologic agents. 8 However, the addition of a single pharmacologic agent to lifestyle modification is unlikely to result in long-term glycemic control. 6,8,9 During the progressive decline in β-cell function that occurs with increasing duration of t2dm, patients will probably require multiple agents with different mechanisms of action and eventually combina tions of drugs that include insulin preparations drug regimes added to lifestyle modification Currently, ~11 classes of agents are available for the treatment of patients with t2dm, and several more classes State University of New York Health Science Center at Brooklyn, Department of Medicine, 450 Clarkson Avenue, Brooklyn, New York, NY 11203, USA. hlebovitz1@ hotmail.com nature reviews endocrinology advance OnLine PuBLiCatiOn 1

2 Key points Lifestyle modification in combination with current pharmacologic therapies can achieve targets of metabolic control in many patients with type 2 diabetes mellitus (T2DM) Factors related to the patient, health-care provider and drug regime can interfere with patients reaching these targets In the USA, control of HbA, blood pressure and lipid values improved 1c during , and were reflected in 30 40% decreases in vascular complications in patients with T2DM Gastric bypass surgery in morbidly obese patients with T2DM causes remission of their diabetes mellitus or marked improvement in hyperglycemia within several weeks of the surgery The mechanisms by which gastric bypass surgery improves diabetes mellitus include dramatic alterations in gastrointestinal hormone secretory patterns Long-term efficacy and safety data from comparative studies are needed to evaluate gastric bypass surgery as a primary therapy for patients with T2DM and a BMI <35 kg/m 2 Box 1 Mechanisms of antidiabetic agents Increase β-cell insulin secretion by a glucose-independent mechanism 16 Sulfonylureas Meglitinides Increase insulin secretion by a glucose-dependent mechanism 22 DPP4 inhibitors 78,79 GLP1 receptor agonists Decrease insulin resistance 23,75 Thiazolidinediones 17,23 Metformin Suppress glucagon secretion by a glucose-dependent mechanism 22 DPP4 inhibitors 78,79 GLP1 receptor agonists 18 Amylin analogs Act within the gastrointestinal tract to lower postprandial glucose excursions α-glucosidase inhibitors Colesevelam Activate brain D2 dopamine receptors to lower plasma levels of glucose 108 Bromocriptine Preparations that provide exogenous insulin 20,26 Basal, mixed and prandial insulins Abbreviations: DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1. are in the late stages of development. Only three classes (insulin, sulfonylureas and biguanides) were available from the mid-1950s through to the mid-1990s. the large number of new classes of agents developed after 1995 reflects the increase in our understanding of the multiple targets for improving hyperglycemia. Currently used antidiabetic agents can be distinguished by their mechanisms of action (Box 1). the primary effect of all these agents is to improve overall glycemic control. this control is achieved with some agents that predominantly lower the fasting plasma glucose level (sulfonylureas, metformin and basal insulins); 16,17 with others that primarily lower postprandial plasma glucose excursions (α-glucosidase inhibitors, meglitinides, pramlintide, exenatide and prandial insulins); and with still others that do both (thiazolidinediones, dipeptidyl peptidase 4 [DPP4] inhibitors, liraglutide and mixed insulins). 20,22 24 Treatment algorithms several treatment algorithms have been proposed for patients with t2dm that differ considerably in their approach. 7,25 One possible scheme takes into account the differing efficacy and safety issues of the antidiabetic agents. in this scheme, after initial failure to achieve target glycemic goals by lifestyle modification and treatment with metformin (the primary first-line drug for t2dm), the prescribing physician can add either an insulin secretagogue or a moderate dose of a thiazolidinedione (for example, 30 mg pioglitazone). the insulin secretagogue could be either a sulfonylurea which is an inexpensive option, although responses to this treatment have limited durability and are associated with an increased risk of hypoglycemia and weight gain or a DPP4 inhibitor, which is an expensive choice, but does not cause weight changes and has a very low incidence of hypoglycemia. the next step in the intensification scheme might be to discontinue the insulin secretagogue and add a glucagon-like peptide (GLP) 1 receptor agonist. Liraglutide could be prescribed if the fasting plasma glucose level is the major issue or exenatide twice daily could be administered if postprandial hyperglycemia is the predominant abnormality. 24 although not yet recommended by the regulatory agencies, adding basal insulin might be the next stage in the treatment regimen. an intensive basal-bolus insulin regimen with insulin sensitizers might be necessary in some patients with t2dm who have not been able to achieve their target glycemic goal with combinations of other agents. 24,26 efficacy of antidiabetic drugs a large amount of information is available on the efficacy of the various antidiabetic regimens used to achieve longterm glycemic control in patients with t2dm. the results from the uk Prospective Diabetes study (ukpds) 6 and the a Diabetes Outcome Progression trial (adopt) 9 showed quite clearly that a patient s response to any one specific antidiabetic agent decreases with time. the authors of these studies suggested that complex regimens with multiple agents that have different mechanisms of action will be required to maintain target goals in the long term. 6,9 the treating to target in type 2 Diabetes (4t) trial, 26 in which various insulin regimens were used to treat patients with t2dm who responded inadequately to oral agents, found that between 49.4% and 67.4% of patients achieved a median level 7% and between 31.9% and 44.7% had a median 6.5% during 3 years of treatment. regardless of the starting insulin regimen (basal insulin, mixed insulin twice daily or prandial insulin), most of the patients 2 advance OnLine PuBLiCatiOn

3 required the addition of another insulin regimen to their therapeutic program to reduce their level. 26 the Liraglutide effect and action in Diabetes (LeaD) 1 6 clinical trials studied the effects of adding liraglutide to the treatment of patients with t2dm who did not respond adequately to various combinations of oral agents. 24,27 31 these six trials demonstrated that of the patients who received 1.8 mg of liraglutide daily for 6 months to 1 year between 42% and 54% achieved a level of 7% and between 21% and 38% achieved an level 6.5%. 24,27 31 similar results were found when exenatide was administered twice daily. 21,32,33 addition of the once-weekly GLP1 receptor agonist exenatide longacting release in patients with t2dm who did not respond adequately to oral agents resulted in 74% of patients achieving an level 7.0%, 54% achieving an level 6.5% and 26% achieving an level 6.0%. 32,34 in three long-term, randomized, controlled, clinical trials that examined the effects of intensive glycemic control on cardiovascular outcomes action to Control Cardiovascular risk in Diabetes (accord), action in Diabetes and vascular Disease (advance) and the veteran affairs Diabetes trial (vadt) mean or median levels of 6.4%, 6.5% and 6.9%, respectively, were maintained for periods of years with combinations of lifestyle modification, oral pharmacologic agents and insulin the conclusion that can be drawn from these studies is that current and near-future antidiabetic therapies are able to achieve an level 7.0% in the majority of patients with t2dm. epidemiologic data from the us national Health and nutrition examination surveys (nhanes) from 1999 to 2006 show that the predictive margin for having levels <7% in patients with type 1 diabetes mellitus (t1dm) or t2dm increased from 37% in to 49.7% in and 55.7% in ; 38,39 this improvement seems to have leveled off in (Figure 1). 39 after controlling for demographic variables and duration of diabetes mellitus, the improvements in mean values between 1999 and 2004 remained statistically significant. 38 these data precede the introduction of GLP1-related therapies, which means that the effect of these therapies is yet to be determined. substantial falls were also seen in systolic and diastolic blood pressures (5.7 mmhg and 8.2 mmhg) and in total cholesterol levels (0.96 mmol/l) in patients with diabetes mellitus (Figure 1). 39 this improvement in cardiovascular risk factors has occurred despite the increase in obesity and reflects improved pharmacotherapy. aggressive management of traditional cardiovascular risk factors with current pharmacologic agents is able to reduce the level of risk to near or at the american Diabetes association target values, as demonstrated in accord and vadt (table 1). 35,37 Clearly, many patients with t2dm can be treated to achieve current metabolic targets with present medical therapies. Effects of improved glycemic control the primary goal of chronic treatment of t2dm is to reduce the incidence of microvascular and macrovascular a HbA 1c (%) b 155 Systolic BP (mmhg) c Total cholesterol (mmol/l) NHANES data complications. the mean level of is a measure of chronic glycemic control and is a surrogate measurement that correlates with clinical outcomes in some, 8,40 but not all, studies Other factors that determine clinical outcomes are previous glycemic control, other metabolic factors, presence of subclinical disease and genetic background Both the Diabetes Control and Complications trial (DCCt) and the ukpds showed that glycemic control as measured by levels of is a major determinant of the incidence of microvascular complications. 8,40 neither, however, showed that improved glycemic control reduced the incidence of premature death or macrovascular disease. By contrast, the steno 2 study showed that reducing all the traditional macrovascular risk factors over 8.5 years did decrease macrovascular disease in patients with t2dm. 45 three large clinical trials (accord, advance and vadt) failed to show a substantial effect of lowering the mean level of by % in reducing cardiovascular events in patients with known t2dm of mean duration Diastolic BP (mmhg) HDL (mmol/l) NHANES data Figure 1 Changes in HbA 1c, blood pressure and serum lipid values in NHANES data from NHANES is a population-based survey that reflects the population of the USA. Levels of a HbA 1c and b systolic and diastolic blood pressure fell progressively from the period to the period and seem to have reached a plateau in c Total cholesterol levels have fallen progressively from through , whereas HDLcholesterol levels have risen only slightly during the same period. Abbreviations: BP, blood pressure; NHANES, National Health and Nutrition Examination Survey. Permission obtained from Elsevier Ltd Hoerger, T. J. et al. Diabetes Res. Clin. Pract. 86, nature reviews endocrinology advance OnLine PuBLiCatiOn 3

4 Table 1 Current aggressive management of traditional cardiovascular risk factors in patients with T2DM 35,37 Measurement AdA target values Accord vadt Baseline on treatment Baseline on treatment LDL cholesterol (mmol/l) HDL cholesterol (mmol/l) >1.04 (men) >1.30 (women) 1.00 (men) 1.23 (women) 1.05 (men) NA (women) Triglycerides (mmol/l) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) HbA 1c (%) Abbreviations: ACCOrD, Action to Control Cardiovascular risk in Diabetes; ADA, American Diabetes Association; NA, not available; T2DM, type 2 diabetes mellitus; vadt, veteran Affairs Diabetes Trial. Diabetic population (%) CVD years and previous cardiovascular events or high cardiovascular risk the epidemiology of Diabetes interventions and Complications (edic) study has shown that the effectiveness of previous glycemic control continues to influence the rate of progression of diabetic complications for many years. 41,46 the conclusions from these and other studies are that decreasing levels of is not always associated with improved clinical outcomes and that the benefit of glycemic interventions might take many years to become evident as improved clinical outcomes. these limitations mean that although a treatment strategy might show an improvement in surrogate markers, such as levels of IHD CHF Stroke Visual loss ESRD Amputations Diabetic complication Figure 2 Change in incidence of diabetic complications in the population of the USA from 1995 to 2003, 2006 or 2007 depending on the data available. The incidence of all vascular complications, except congestive heart failure, has seen a striking drop. The baseline levels of each complication in 1995 per 1,000 patients with diabetes mellitus (type 1 and type 2) were as follows: 76.7 for CvD; 36.0 for IHD; 19.5 for CHF; 13.4 for stroke; 7.6 for amputations. The baseline levels in 1995 were 23.7% for visual loss and 310.9/100,000 diabetic patients for ESrD. Abbreviations: ESrD, end-stage renal disease; CHF, congestive heart failure; CvD, cardiovascular disease; IHD, ischemic heart disease. Data are from US Center for Disease Control website. 47, the proof that the improvement is meaningful requires measurements of clinical outcomes. Diabetic complications the us Center for Disease Control (CDC) collects data annually on the health of the country s population and provides information on the rates of each type of diabetic complication per 1,000 patients with diabetes mellitus (both type 1 and type 2). the incidence of all diabetic complications increased progressively (approximately doubling) from 1980 to since 1996, the rates of all diabetic complications, except congestive heart failure, have gradually declined (Figure 2). 47 the incidence of total cardiovascular disease and ischemic heart disease decreased by 26.5% and 40.1%, respectively, from 1995 to 2003, and the incidence of stroke decreased by 35.1% from 1995 to according to the CDC data, the incidence of visual loss decreased by 26.6% from 1995 to 2007 and that of end-stage renal disease decreased by 34.3% from 1995 to amputations declined by 48.7% during these results indicate that medical therapy of patients with diabetes mellitus, which has improved dramatically since 1995, has resulted in clinical benefits. the great difficulty in evaluating the clinical benefits of our current therapies is that we will not know their outcomes for years. 41,45,46 Limitations of current therapies Despite the availability of good medical treatment strategies for patients with t2dm, the majority of patients are far from achieving the combined target goals for glycemic, blood pressure and lipid levels (table 1). 38,39 the factors accounting for this deficit can be broken down into patient-related issues, health-care provider issues, treatment inadequacies and adverse effects. Patient-related issues Both t1dm and t2dm present considerable challenges for patients, as they demand substantial efforts in selfmanagement and personal discipline. understandably, these factors are major barriers to achieving target goals for glycemic, blood pressure and lipid levels the patient might be reluctant to take certain medications that could be beneficial, such as insulin or injectable GLP1 receptor agonists; have poor or variable compliance 4 advance OnLine PuBLiCatiOn

5 with medications; might discontinue effective medications because of misleading reports from the public media; and have emotional and behavioral issues that impede their treatment. Many patients with t2dm interpret the need to start insulin therapy as a sign of their failure and a worsening of their condition; they also fear the adverse effects of weight gain and hypoglycemia. 48 these patients often view insulin therapy as being more restrictive to their daily life than lifestyle modifications with oral agents and believe that having to take insulin changes other people s view of them. 48 noncompliance with medications and diet modification is a major issue in the management of patients with t2dm. a study of 122,967 patients with t2dm who received their care through Kaiser Permanente northern California, usa, and were not using insulin, were assessed for their adherence to therapy. 49 During 2005, 53% had an level above target, 53% were above target for hyperlipidemia and 47% were above target for blood pressure. Poor adherence was defined as a weighted nonadherence measure of 20% across all medications prescribed for that condition. within the above-target patients, 23% had poor adherence to their oral antidiabetic medications, 21% had poor adherence to their hyperlipidemia medications and 20% had poor adherence to their antihypertensive medications. in a study in the usa of 502 adults taking insulin, some intentional omission of insulin was reported in >50% of the participants and regular omissions were reported in 20%. 50 Health-care provider issues the attitudes and behavior of health-care providers can also be a barrier to patients with t2dm achieving target glycemic goals. treating hyperglycemia is a much greater challenge to the health-care provider than treating hypertension or hyperlipidemia. antidiabetic therapy is dependent on lifestyle modification, oral agents (which can have considerable adverse effects) and injectable therapies, such as insulin preparations and GLP1 receptor agonists. antidiabetic therapy is also affected by a progressive loss of endogenous β-cell insulin secretory function. the health-care provider must not only reinforce a healthy lifestyle but must choose which agents to use, and decide when to intensify the treatment by increasing the dose of the current agent or adding additional agents. studies have shown that health-care providers display considerable inertia towards intensifying antidiabetic therapy. 49,51 in the Kaiser Permanente study, intensification of therapy for each metabolic component of t2dm was defined as an increase in the number of drug classes used; an increase in the daily dose of at least one ongoing medication in a given drug class; or a switch to a medication in a different class. 51 the authors determined that intensification of therapy was required in patients with levels of 8.0%, LDL cholesterol 3.37 mmol/l, and systolic blood pressure 140 mmhg. those values were found in 29%, 20%, and 22% of patients, respectively. However, treatment intensification actually occurred in only 36 54% of the patients who required it. 51 similarly, when the american Diabetes association target goals of these parameters (table 1) were exceeded, intensification of therapy occurred in only 32 47% of patients. 51 the inertia of physicians is much greater when the decision whether to add injectable insulin or GLP1 receptor agonists is contemplated, as adding an injectable agent to a patient s other treatment is a major decision. Many studies document the factors associated with a healthcare provider s resistance to starting insulin therapy. 52 the Diabetes attitudes, wishes and needs (Dawn) study found that 65% of health-care providers were reluctant to start insulin therapy in their patients because of their perception of the patient s concerns about the negative aspects of insulin therapy. 48 Physicians are also reluctant to start insulin therapy in their patients because of the belief that compliance will be poor. 53 Treatment inadequacies and adverse effects none of the currently available pharmacologic agents used to treat patients with t2dm has been demonstrated to stop the progressive decline of pancreatic β-cell function and insulin secretion. 6,9 Consequently, single agents and combination therapies are able to achieve target glycemic goals for limited periods of time and only in a subset of patients with t2dm in the clinical trials that prescribed the most intensive glycemic control strategies available, such as accord, some patients with t2dm still could not achieve a level of 7%. 54 the degree to which a pharmacologic agent will decrease the level of depends on the patient s baseline level of this parameter. 56 agents that decrease the fasting plasma glucose level, such as sulfonylureas and metformin, can decrease the level of by ~2.0% in patients with a baseline level >9.0% and by ~0.5% in those with a baseline level <7.5%. agents that only decrease postprandial glucose excursions, such as α-glucosidase inhibitors or nateglinide, will decrease the level of by %. Pharmacologic treatment of patients with t2dm is limited not only by the efficacy of the agents but also by their adverse effects (Box 2), 55,57 72 some of which are discussed below. theoretically, insulin preparations should be able to lower in patients with t2dm to any desired level. However, the nonphysiologic route of administration and the prolonged duration of action of the available insulin preparations, coupled with the large doses needed to overcome insulin resistance, preclude mimicking physio logic insulin secretion. 73,74 the incidence of moderate and severe hypoglycemia increases progressively as insulin treatment regimens aim to reduce the level of from 7.5% to 6.0%. 35,37,62,66 Progressive weight gain that might exceed 10 kg is associated with increasingly intensive insulin treatment. 35,63,64 Other concerns about insulin therapy have been raised in some clinical and observational studies, but are poorly understood. these concerns include the possibility of an increased incidence of some cancers 65 and an increase in long-term mortality and cardiovascular events in patients with t2dm who have had severe hypoglycemic episodes. 37,61,66 thiazolidinediones are very effective in decreasing insulin resistance and in combination with other agents nature reviews endocrinology advance OnLine PuBLiCatiOn 5

6 Box 2 Safety issues with antidiabetic agents sulfonylureas Hypoglycemia weight gain Possible increased mortality from cardiovascular disease Possible increased incidence of cancer Metformin Gastrointestinal symptoms such as abdominal discomfort, diarrhea, anorexia and nausea Lactic acidosis (with impaired renal function) vitamin B deficiency 12 glucosidase inhibitors Gastrointestinal discomfort Borborygmi (stomach growling or rumbling) Thiazolidinediones Fluid retention Edema Congestive heart failure weight gain Bone fractures Possible increased risk of ischemic heart disease (with rosiglitazone) dpp-4 inhibitors Possible association with acute pancreatitis Possible association with exfoliative dermatitis Increased respiratory infections insulin Marked weight gain Severe hypoglycemia Increased cancer incidence incretin mimetics Nausea and vomiting Possible association with medullary thyroid cancer (liraglutide) Possible association with acute pancreatitis (exenatide and liraglutide) can effectively reduce levels of. 75 their effects in lowering levels are more durable than those of sulfonyl ureas, metformin or DPP4 inhibitors. 9,67 However, thiazolidinediones can induce fluid retention, which in a few patients precipitates congestive heart failure. 68,69 in addition, long-term therapy with thiazolidinediones has been associated with an increase in the incidence of bone fractures, particularly in women. 69,70 thiazolidinediones increase peripheral adipose tissue mass. 23,69 Considerable controversy exists concerning the safety of rosiglitazone, which has been associated with adverse cardiovascular events. 76 an FDa advisory panel reviewed this issue in July 2010 and recommended strengthening the warning about potential increases in the incidence of ischemic heart disease in patients taking rosiglitazone. 77 the final decision of the FDa was for the drug s sponsor to submit a risk evaluation and Mitigation strategy and its provisions will restrict the use of rosiglitazone to new patients who are informed of the potential risk and who cannot achieve adequate glycemic control using other agents and in consultation with their health-care professional decide not to take pioglitazone for medical reasons. 77 the european Medicines agency is phasing out the use of rosiglitazone. GLP1 receptor agonists are unique among anti diabetic agents in that they increase insulin and decrease glucagon secretion only when plasma glucose levels are raised. 22,78,79 they delay gastric emptying and increase satiety, which causes reduced food intake and modest weight loss. 22,78,79 use of GLP1 receptor agonists is associated with nausea and vomiting; although these symptoms generally lessen with continued treatment, 24,32,79 in 5 15% of patients they will be severe enough to require cessation of the agent. 24,27,30 the FDa has additional concerns about the possibility that GLP1 receptor agonists are associated with acute pancreatitis and thyroid medullary carcinoma. 71 analyses of large health-care databases show that the incidence of acute pancreatitis is increased in patients with obesity and t2dm and that the prevalence of acute pancreatitis is no greater in patients with diabetes mellitus who are taking exenatide or sitagliptin than in those taking sulfonyl ureas or metformin. 72 thyroid medullary carcinomas were observed in rats and mice treated with liraglutide, however, no such tumors have been observed in patients taking this drug. 71 Bariatric surgery the concept of surgery as a primary therapy for t2dm rather than for obesity raises many questions and issues. Bariatric surgery is the only effective treatment for morbidly obese patients. although true randomized, comparative clinical trials have not yet been done, the available data suggest that the clinical benefits of bariatric surgery far outweigh the risks of complications in morbidly obese individuals the same might not be true of surgery as a primary treatment for patients with t2dm. Before surgical treatment of patients with t2dm can be recom mended, studies are required to establish whether surgical procedures provide at least equivalent improvements in metabolic parameters in these patients to those achieved with current medical therapies, and whether these metabolic changes are associated with improved clinical outcomes. in addition, the long-term complications of the surgical procedures must be identified and weighed against the potential benefits. selection criteria for surgical treatment of patients with t2dm must also be established. results from bariatric surgical procedures in patients with a BMi 35 kg/m 2 (some of whom also had t2dm) have been reviewed in several meta-analyses and publications. 2,83,84 Major problems with the data available from studies of bariatric surgery are that the studies are observational and the data are frequently analyzed retrospectively; the studies were not controlled and the baseline data were not collected in a uniform manner; the long-term follow-up data were limited and considerable numbers of patients were lost to follow-up; and only one, small study had a randomized, controlled design. 85 Despite the limitations of these data, several studies have compared long-term mortality and morbidity in morbidly obese individuals who have undergone bariatric 6 advance OnLine PuBLiCatiOn

7 Table 2 Meta-analysis findings on the effects of bariatric surgery on weight and T2DM resolution 2 surgery Absolute weight loss (kg) excess body weight loss (%) resolution of T2dM (%) no improvement or worsening of T2dM (%) Gastric banding Gastric bypass Biliopancreatic diversion 56.3 NA The total population comprised 135,246 patients with a mean age of 40.2 years and a mean BMI of 47.9 kg/m % of the patients had T2DM. Abbreviations: NA, not available; T2DM, type 2 diabetes mellitus. surgery to those who have not. 80,81,86 88 all the studies have been interpreted to show that bariatric surgery reduces mortality (relative risk depending on the study and duration of follow-up) 80,81,86 88 and is associated with much better clinical outcomes than traditional nonsurgical management of morbid obesity. 81,87,88 as a result, the current recommendations are that bariatric surgery is indicated in appropriate patients (those with no contraindications, such as noncompliance or risk of surgical complications) with BMi 40 kg/m 2 or in patients with BMi 35 kg/m 2 who have comorbidities such as diabetes mellitus or sleep apnea. 89,90 as t2dm is very frequent in obese individuals, many of the patients (22%) undergoing bariatric surgery had been treated for t2dm. 2,84,87,91,92 as would be anticipated, major weight loss over the months after bariatric surgery was accompanied by marked improvements in metabolic control, leading to decreased use of antidiabetic medications as well as remission of the t2dm. this association between the degree of improvement in control of t2dm and the extent of weight loss is characteristic of bariatric procedures that restrict food intake. 2,5,84,87,92,93 diversionary and restrictive procedures several gastrointestinal operations have been developed that induce sufficient weight loss to reduce the clinical consequences of morbid obesity. 3,5,84,86 88,91 these include procedures that restrict food intake into the stomach, such as vertical banded gastroplasty and laparoscopic adjustable gastric banding (LaGB); procedures that both restrict the size of the stomach and divert nutrients directly into the small intestine, such as rygb; and procedures that primarily create malabsorption, such as biliopancreatic diversion. 3,5,83 these procedures have been very effective in reducing body weight and ameliorating obesity-related morbidities and longterm mortality. 5,80 82,85 88 the weight loss is greater and more sustained with the diversionary procedures (mean weight loss >25% and sustained for >10 years) than with the exclusively restrictive procedures (mean weight loss ~15%, with considerable weight regain or reoperation within 5 years). in a 10-year follow-up of 1,703 participants in the multicenter swedish Obese subjects (sos) study, the mean weight loss was 25.0 kg following rygb, 13.2 kg after adjustable gastric banding and 16.5 kg after vertical gastric banding. 87 Bariatric surgery using diversionary procedures, such as rygb, result in a much more rapid improvement in glycemic control and an appreciably greater rate of remission of t2dm than do the restrictive procedures. the highest remission rate is seen following bilio pancreatic diversion. 2,5,84 remission of t2dm is usually, though not always, defined as a fasting plasma glucose level and level in the normal range ( %) without the use of antidiabetic medications. a meta-analysis published in 2009 evaluated the effects of the major bariatric surgical procedures on weight loss and control of t2dm (table 2). 2 the greatest improvement is seen following biliopancreatic diversion, which is associated with a diabetes remission rate of ~95% and a mean weight loss of ~38 40%. the majority of patients with t2dm who do not go into remission have some improvement in their diabetic control after surgery. in many patients with t2dm who undergo rygb, resolution or marked improvement of their hyperglycemia occurred within days or weeks of the surgery and before they had notable weight loss. these observations suggest that diversionary procedures improved t2dm by mechanisms other than simple weight loss. Pories et al. 93 reported in 1995 that gastric bypass surgery led to improvements in t2dm, and these favorable results have subsequently been confirmed by several studies (table 3). 91,94,95 comparison of lagb and rygb procedures a meta-analysis of 14 studies that compared the results of LaGB to those of rygb provides some basis for evaluating the relative merits and issues concerning these two widely-used procedures. 96 this meta-analysis is limited, however, by the quality of the individual studies (only one was randomized and only two matched patients for known predictors of outcome). the authors concluded that loss of excess body weight is consistently greater with rygb than LaGB (mean difference 26%); resolution of co morbidities is greater with rygb than LaGB; operating time and length of hospitalization were greater with rygb than LaGB; perioperative complications were more common with rygb than LaGB (9% versus 5%), whereas long-term reoperation rates were lower with rygb than LaGB (16% versus 24%). 96 the authors concluded that the better weight loss and the lower long-term complication rate of rygb compared to LaGB makes it the preferable surgical procedure to treat obesity. this conclusion is supported by the meta-analyses. 2,84,92 Mechanisms the proposed mechanisms that could be responsible for the postoperative improvement in t2dm are decreased caloric intake, weight loss and changes in the secretory patterns of gastrointestinal hormones and metabolic factors. 5, the reduction of food intake following nature reviews endocrinology advance OnLine PuBLiCatiOn 7

8 Table 3 The effects of rygb procedures on weight loss and resolution of T2DM study n T2dM or glucose intolerance Follow-up (n, time) Schauer et al. 1, (21%) 191 (80%) (2003) 91 (19.7 months) Kim & richards (1 year) (2010) (2 4 years) Lee et al. (2008) BMI <35 kg/m BMI kg/m 2 43 BMI >45 kg/m (24.5%) weight loss (%) effect on T2dM 31.5 FPG and HbA 1c normalized in 83% and markedly improved in 17%; insulin reduction in 78%; oral agent reduction in 80% 32 FPG mmol/l, HbA 1c % FPG 5.88 mmol/l, HbA 1c 6.1% NA, 5 years 32 Treatment goal met in 76.5% Treatment goal met in 92.4% NA Abbreviations: FPG, fasting plasma glucose; n, number of patients; NA, not available; rygb roux-en-y gastric bypass; T2DM, type 2 diabetes mellitus. surgery would lead to decreases in the fasting plasma glucose level and postprandial glucose excursions, and a slow, progressive decline in levels of over a period of several months. the progressive loss of weight would decrease insulin resistance and improve glycemic control. Both of these mechanisms occur following restrictive procedures and probably account for the improvement in t2dm after LaGB. 85 However, these mechanisms cannot account for the observed differences between the effects of rygb and LaGB on glycemic regulation in patients with t2dm. Gastrointestinal rearrangements, such as those that occur in diversionary procedures, lead to striking changes in the secretory patterns of many gastro intestinal hormones. 5, several hypotheses have been proposed to explain the mechanisms by which gastrointestinal diversionary procedures could influence the metabolic abnormalities of t2dm. Laferrère et al. compared the effects of surgery 1 month after rygb to the effects of an equivalent diet-induced weight loss in obese women. 4 the decreases in the fasting plasma glucose level were comparable; however, postprandial plasma glucose levels were significantly lower after rygb than with diet-induced weight loss (7.22 ± 1.62 mmol/l versus 9.62 ± 2.34 mmol/l, P = 0.001). total plasma levels of GLP1 after oral glucose increased sixfold and the measured incretin effect increased fivefold after rygb but did not increase after diet-induced weight loss. 4 numerous studies have demon strated that diversionary procedures are associated with markedly exaggerated secretory responses of GLP1, peptide YY and glucose-dependent insulinotropic polypeptide to meal ingestion. 5, the difference in the improvements in t2dm after diversionary procedures compared to restrictive procedures could be related to the increased secretion of these hormones. the changes in ghrelin (a hormone that stimulates hunger and is secreted by the gastric fundus) secretion following rygb surgery that have been reported are inconsistent; some reports show a decrease and others show no effect. 4,98,100 Benefits the benefits accrued from the treatment of patients with morbid obesity by bariatric surgery considerably exceed the complications of the surgery, which include operative mortality, perioperative and postoperative complications and long-term nutritional and metabolic consequences. 3,5,86,88 this finding is largely attributable to the lack of any long-term effective lifestyle or medical treatment for the morbidly obese patient. this limitation does not apply when considering the role of bariatric surgery as a primary treatment for t2dm in overweight and obese individuals. in this case, a careful consideration of the benefits versus the potential complications of the surgical procedures must be viewed in light of the availability of the effective lifestyle and pharmacologic treatments presented earlier. One noncontrolled study compared mortality and prog ression of disease in 154 morbidly obese patients with t2dm (BMi 35 kg/m 2 ) who had been treated by rygb surgery to 78 patients matched for age, weight, sex and hypertension who had been treated medically. 101 in this retrospective analysis, the mean follow-up for the surgical patients was 9.0 years and that for the medical patients was 6.2 years. Mortality in the patients who underwent surgery was 9% (1% per year) and in the patients treated medically was 28% (4.5% per year). Mean plasma levels of glucose fell from mmol/l to <7.77 mmol/l and antidiabetic medication use decreased from 31.8% to 8.6% in the patients who underwent surgery. By contrast, antidiabetic medication use increased from 56.4% to 87.3% in the patients treated medically. 101 a 2-year randomized, controlled study that compared the results of LaGB to conventional medical treatment in 60 patients with t2dm reported remission of diabetes mellitus in 73% of the surgical group and 13% of the medical group. 85 Mean weight loss was 20.7% in the surgical group and 1.7% in the medical group. remission of t2dm correlated with the extent of weight loss (r 2 = 0.46) and with low baseline levels of. risks and complications the literature does not include sufficient data to define the risks and complications of bariatric surgery specifically in the primary treatment of patients with t2dm. Mortality data for bariatric surgery in morbidly obese patients are available from two major sources. 3,5,92 Buchwald et al. published a meta-analysis in 2007 (table 4). 92 their analysis suggests that postoperative (<30 days) mortality rates for both restrictive and restrictive malabsorptive procedures are <0.5% and following laparoscopic pro cedures are <0.2%. the corresponding values for patients with t2dm were considerably higher, 8 advance OnLine PuBLiCatiOn

9 but the number of patients for whom data were available is quite small (676 patients). a summary of data supplied in the applications for Bariatric Centers of excellence (table 5) provides a little more insight into what complications can be expected following bariatric surgery. 3 Mortality continues to increase up to 90 days after surgery. readmission and reoperation rates during a long-term follow-up are substantial (4.75% and 2.15%, respectively). an evaluation published in 2010 of adverse outcomes in the 30 days following rygb in the assessment of Bariatric surgery (LaBs) study showed that the risk of complications decreases by 10% for every 10 procedures per year increase in volume that the operating surgeon had performed. 102 the complications following bariatric surgery fall into two groups acute and long-term. 3,5,93 the acute complications occur in 5 10% of patients and include hemorrhage, obstruction, anastomotic leaks, infections, rhabdomyolysis, arrhythmias and pulmonary emboli. Long-term complications include neuropathies attributable to nutritional deficiencies, internal hernias, anastomotic stenoses, a variety of mineral and vitamin deficiencies, protein malnutrition, emotional disorders and (infrequently) severe hypoglycemia. the patient who undergoes bariatric surgery must be carefully monitored and in most instances treated with dietary supplements (vitamin B 12, calcium plus vitamin D, folic acid, thiamine, iron, zinc and magnesium) to prevent the many nutritional disturbances and the increased risk of gallstones that can occur. 5, this monitoring and treatment is particularly required following diversionary and malabsorptive procedures. Monitoring these patients for potential long-term complications of bariatric surgery clearly requires continued observation. 5 Unresolved issues surgical treatments could potentially offer patients with t2dm some unique benefits. Hormonal and metabolic changes associated with gastric bypass surgery might be able to restore β-cell mass or function in patients with t2dm. 106 a syndrome of hyperinsulinemic hypoglycemia has been reported to occur several years after gastric bypass surgery in some patients without diabetes mellitus who are treated for morbid obesity. 106 Histology of the pancreatic islets of Langerhans has shown pathology varying from hyperplasia of the β cells to nesidioblastosis. 106 Conclusions Medical therapy for patients with t2dm has improved considerably during the past decade. a substantial percentage of patients with t2dm can achieve target glycemic control with minimal adverse effects from their medical treatment. the other metabolic abnormalities associated with t2dm, such as lipid disturbances and hypertension, are also amenable to medical therapy. this finding is of course in great contrast to the failure of medical therapy to treat morbid obesity; therefore, the assessment of bariatric surgery versus medical therapy for the treatment of the patient with t2dm must compare Table 4 Operative complications from bariatric surgery surgery type death 30 days death >30 days to 2 years Restrictive* n/n % n/n % Open 32/9, / Laparoscopic 23/19, /5, Restrictive and/or malabsorptive* Open 61/12, /3, Laparoscopic 42/19, /6, Malabsorptive* Open 53/5, /1, Laparoscopic 4/ NA NA Patients with type 2 diabetes mellitus Open and laparoscopic 8/ / Data from a meta-analysis. *Overall mortality. Abbreviations: n, number of patients who died; N, total number of patients in the study; NA, not available. Table 5 Surgical review Corporation* data from 272 ASMBS Centers of Excellence 3 setting number of patients Percentage Hospital mortality Mortality 30 days after operation Mortality 90 days after operation readmissions 1, reoperation *The Surgical review Corporation is an independent nonprofit organization to manage the Centers of Excellence programs (495 surgeons and 110,000 patients). Abbreviation: ASMBS, American Society for Metabolic and Bariatric Surgery. the relative effectiveness of each approach to the safety of each. the bariatric surgery literature indicates that the mortality and complication rates have steadily declined with the development of improved techniques and training and the establishment of standards for the centers of excellence in bariatric surgery that have been created. 5,96 However, operative mortality of % and consider able rates of acute and late complications persist. 3 adequate data on mortality and complications in a population of patients with t2dm is lacking. the scant data from the meta-analysis of Buchwald et al. indicate that surgical mortality and morbidity might be higher in the diabetic population than in the obese population. 2 although all bariatric surgery procedures improve t2dm by promoting weight loss, gastric bypass surgery and duodenal exclusion procedures seem to provide the best balance between complications and improvement in hyperglycemia and other metabolic abnormalities in patients with t2dm. 3,5,96 this improvement occurs in patients with BMi <35 kg/m 2 as well as those with BMi >35 kg/m 2. 5,95 the mechanism, though not absolutely defined, seems to be largely related to changes in gastrointestinal hormone secretion and metabolic factors. the majority of patients with t2dm who undergo bariatric surgical procedures seem to have a remission in their hyperglycemia and the remainder show considerable improvement. the patients who have the best resolution nature reviews endocrinology advance OnLine PuBLiCatiOn 9

10 of their t2dm seem to be those who have t2dm of short known duration, are on dietary or oral antidiabetic agent therapy, lose the most weight 80,83,85,93 and undergo a diversionary procedure. 96 Patients who are severely insulindeficient and not obese are least likely to have resolution of their t2dm. 91 How surgical therapy of patients with t2dm is placed in relation to medical therapy needs to be established. as surgery does still carry an increased risk of mortality and morbidity, considering bariatric surgery only for those patients with t2dm who are unable to achieve their targeted metabolic control on medical therapy seems to be a reasonable approach. the most appropriate candidates for surgery would be those with a BMi >35 kg/m 2. For individuals with a BMi kg/m 2, surgical therapy could be considered only if no other effective way exists to manage their condition. ideally, long-term, randomized, controlled clinical trials of surgical versus medical therapy should be carried out in patients with t2dm whose BMi is kg/m 2. a trial of this kind would be the best means to compare the relative efficacy and adverse effect profiles of the treatment modalities. unfortunately, randomization to long-term medical versus surgical treatment for t2dm might not be acceptable to patients. However, long-term outcomes can be compared in populations of patients with t2dm who are matched for baseline metabolic and clinical status and treated surgically or medically at the same centers under uniform protocols. such data are necessary if we hope to define appropriate selection criteria for surgical therapy. until such data are available, interventional therapy for t2dm can only be decided empirically on an individual patient basis. Review criteria PubMed was initially searched to identify peer-reviewed articles published in for bariatric surgery and for type 2 diabetes mellitus (T2DM) and its treatments. The search terms used (either alone or in combination) were T2DM, treatment, glycemic control sulfonylureas, metformin, thiazolidinediones, rosiglitazone, optimal insulin, DPP4 inhibitors, GLP1 agonists, clinical outcomes, clinical trials, bariatric surgery, complications, obesity, gastric band and gastric bypass. The articles selected for discussion in this review were predominantly in English, focused on humans and related to clinical trials, editorials, letters, meta-analyses and randomized, controlled trials. 1. DeFronzo, r. A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, Buchwald, H. et al. weight and type 2 diabetes after bariatric surgery: systemic review and meta-analysis. Am. J. Med. 122, Pories, w. J. Bariatric surgery: risks and rewards. J. Clin. Endocrinol. Metab. 93 (Suppl. 1), S89 S96 (2008). 4. Laferrère, B. et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 93, (2008). 5. rubino, F., Schauer, P. r., Kaplan, L. M. & Cummings, D. E. Metabolic surgery to treat type 2 diabetes: clinical outcomes and mechanisms of action. Annu. Rev. Med. 61, (2010). 6. Turner, r. C., Cull, C. A., Frighi, v. & Holman, r. r. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes. Progressive requirement for multiple therapies (UKPDS 49). JAMA 281, (1999). 7. Nathan, D. M. et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32, [No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study Group. Lancet 352, (1998). 9. Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, (2007). 10. [No authors listed] UK prospective diabetes study 16. Overview of 6 years therapy of type II diabetes: a progressive disease. UK Prospective Diabetes Study Group. Diabetes 44, (1995). 11. Ferrannini, E. et al. β-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J. Clin. Endocrinol. Metab. 90, (2005). 12. Marchetti, P., Dotta, F., Lauro, D. & Purrello, F. An overview of pancreatic beta-cell defects in human type 2 diabetes: implications for treatment. Regul. Pept. 146, 4 11 (2008). 13. Yki-Järvinen, H. et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann. Intern. Med. 30, (1999). 14. Yki-Järvinen, H. Combination therapies with insulin in type 2 diabetes. Diabetes Care 24, (2001). 15. riddle, M. C., rosenstock, J. & Gerich, J. The treat-to-target trial. randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26, (2003). 16. Lebovitz, H. E. in Diabetes Mellitus: A Fundamental and Clinical Text 3 rd edn Ch. 76 (eds Leroith, D., Taylor, S. I. & Olefsky, J. r.) (Lippincott williams & wilkins, Philadelphia, PA, 2004). 17. Hundal, r. S. & Inzucchi, S. E. Metformin: new understandings, new uses. Drugs 63, (2003). 18. Lebovitz, H. E. Adjunct therapy for type 1 diabetes mellitus. Nat. Rev. Endocrinol. 6, (2010). 19. Hanefeld, M. Cardiovascular benefits and safety profile of acarbose therapy in prediabetes and established type 2 diabetes. Cardiovasc. Diabetol. 6, 20 (2007). 20. Holman, r. r. et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N. Engl. J. Med. 357, (2007). 21. Heine, r. J. et al. Exenatide versus glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann. Intern. Med. 143, (2005). 22. Drucker, D. J. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 30, (2007). 23. Lebovitz, H. E. & Banerji, M. A. Treatment of insulin resistance in diabetes mellitus. Eur. J. Pharmacol. 19, (2004). 24. Buse, J. B. et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26- week randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374, rodbard, H. w. et al. Statement by an American Association of Clinical Endocrinologists/ American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr. Pract. 15, Holman, r. r. et al. Three year efficacy of complex insulin regimens in type 2 diabetes. N. Engl. J. Med. 361, russell-jones, D. et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met + SU): a randomized trial. Diabetologia 52, Zinman, B. et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met + TZD). Diabetes Care 32, Garber, A. et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomized, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373, Nauck, M. et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 32, Marre, M. et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 10 advance OnLine PuBLiCatiOn