**5. Trials proving the efficacy of bariatric surgery in diabetes control**

Obesity and type 2 diabetes mellitus are both major health problems due to growing incidence and increasing costs of care [46]. Type 2 diabetes mellitus closely follow incidence and prevalence of obesity and the evolution of the disease is marked by several complications such as retinopathy and blindness, neuropathy and lower limb amputations, end stage renal disease, myocardial infarction and stroke if the disease is not well controlled. Despite of tremendous progressions which have been made in type 2 diabetes mellitus treatment, more than fifty percent of patients do not reach their glycemic control targets [47].

There are a number of **observational trials** and published meta-analyses that demonstrate consistent improvement of type 2 diabetes after metabolic surgery. In an observational controlled study from Norway, morbidly obese patients with mean BMI 45.1 kg/m2 were treated with either Roux-en-Y gastric bypass or intensive medical therapy. At one year weight loss was 30% in surgery group compared with 8% in lifestyle group and diabetes remission rate was 70% versus 33%. [48]

A meta-analysis of studies on type 2 diabetes obese patients who underwent different types of bariatric procedures showed at baseline the mean age 40.2 years, body mass index was 47.9 kg/m2 , 80% were female, weight loss overall was 38.5 kg or 55.9% excess body weight loss and an overall rate of remission of diabetes of 78%. [49] Remission of diabetes occurred in half of patients who underwent laparoscopic adjustable gastric bypass, 80% of patients who underwent Roux-en-Y gastric bypass, and 95% of those who underwent biliopancreat‐ ic diversion. [49]

The key results from the Swedish Obese Subjects (SOS) study have been published in a review. This is a long term, prospective, controlled trial on 2010 obese subjects who underwent metabolic surgery (13% gastric bypass, 19% banding and 68% vertical banded gastroplasty) and 2037 matched obese control subjects receiving usual care. [50] The diabetes remission rate was increased several fold at 2 years (adjusted OR=8.42) and 10 years (adjusted OR=3.45). After 2 years of follow-up, 72% of SOS patients with type 2 diabetes mellitus at baseline were in remission in the surgery group. But amongst patients who underwent surgery with remission of diabetes at 2 years, 50% had relapsed after 10 years. [50]

The outcomes of bariatric surgery are analyzed in a retrospective case-matched study com‐ paring medical treatment, duodenal switch, and laparoscopic adjustable gastric band to Rouxen-Y gastric bypass for treatment of obese type 2 diabetes. [51] At one year of follow-up the Roux-en-Y gastric bypass produced greater weight loss, A1c improvement, and higher diabetes medication score reduction than medical therapy and laparoscopic adjustable gastric bypass but duodenal switch produced greater reduction in A1c and diabetic medication score than Roux-en-Y gastric bypass. [51]

Recently more and more evidences come from **randomized controlled trials**. These studies are difficult to be compared because of different inclusions criteria regarding the mean age, duration of diabetes, mean BMI and different primary endpoints and also lack of homogenous definition of diabetes remission. The first randomized controlled trial conducted on a small group compared conventional diabetes therapy consisting on weight loss by lifestyle changes versus laparoscopic adjustable gastric banding associated to diet on 60 obese patients (BMI >30 and <40) with recently diagnosed type 2 diabetes [52]. After two years of follow-up, remission of type 2 diabetes defined by fasting glucose level <126 mg/dl and glycated hemo‐ globin value <6.2% without glycemic therapy, was achieved by 73% in surgical group and by 13% in the conventional group. [52] As the authors recognized, this study has several limita‐ tions: relatively small number of patients, limited time of follow-up thus the results cannot be extrapolated for a longer period, lack of hard end points such as mortality and cardiovascular events [52].

A higher number of patients, 150 were included in Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently trial (STAMPEDE trial) and were randomly assigned to intensive medical therapy alone or intensive medical therapy plus either Roux-en-Y gastric bypass or sleeve gastrectomy. [53] These patients had a longer duration of diabetes, >8 years and mean BMI was 36 and glycated hemoglobin at baseline range from 8.9% to 9.5%. At 12 months of follow-up the target glycated hemoglobin level <6% was achieved by 12% in the intensive medical therapy alone group versus 42% in the gastric-bypass group and 37% in the sleeve-gastrectomy group, without significant differences between surgical groups. [53] Glycated hemoglobin and fasting plasma glucose improved significantly faster and at a great magnitude at three months in surgical groups compared with medical therapy group with a lower use of antidiabetic agents and this improvement was sustained over the entire followup period. [53] Type 2 diabetes mellitus control was significantly improved after both bariatric surgery procedures with a reduction of glycated hemoglobin by 2.9 percentage points. The average number of diabetes medications per patient per day increased in intensive medical therapy from 2.8 at baseline to 3 at one year and decreased in surgical groups from 2.6 (Rouxen-Y bypass group) and 2.4 (Sleeve gastrectomy group) to 0.3 and 0.9 respectively. [53] Insulin treatment at 12 months of follow-up was more prevalent among patients on intensive medical therapy group 38% versus gastric by-pass group 4% and sleeve-gastrectomy group 8%. [53] Not only glycemic control was improved secondly bariatric surgery but also HOMA-IR index, CRP level, lipid profile, with significantly decreased of triglycerides and increased of highdensity lipoprotein (HDL) cholesterol. The main limitation of this study, short duration of follow-up is overcome by another study with a follow-up period of two years, performed on 60 obese (BMI over 35), type 2 diabetic patients randomized on medical therapy, laparoscopic gastric bypass and biliopancreatic diversion. [54] In this study remission of diabetes was defined by fasting plasma glucose level of less than 100 mg/dl (5.6 mmol/l) and glycated hemoglobin level of less than 6.5% for at least one year without antidiabetic agents. At two years of follow-up the remission of diabetes occurred in 75% of patients in gastric bypass group, 95% of patients in biliopancreatic diversion group and none of patients in medical therapy group. [54] The relative risk of diabetes remission was 7.5 in the gastric-bypass group and 9.5 in the biliopancreatic-diversion group as compared with the medical-therapy group. [54] The average time to the normalization of fasting glucose and glycated hemoglobin was 10 months for gastric bypass versus 4 months for biliopancreatic diversion, differences being significant. [54] Biliopancreatic diversion and gastric bypass are much more effective in controlling glycemia in type 2 obese diabetes patients than medical therapy. [54] The Diabetes Surgery Study compared Roux-en-Y gastric bypass versus medical therapy in achieving a composite endpoint consisting in cardiovascular risk factors, glycated hemoglobin under 7%, LDL cholesterol under 100 mg/dl and systolic blood pressure under 130 mg/dl. [55] At 12 months, 19% in the medical group and 49% in the gastric bypass group achieved the primary composite endpoint. [55]

Glycated hemoglobin was significantly improved at follow-up visit in all groups who under‐ went a surgical procedure compared with medical group. In the Diabetes Surgery Study the mean A1c at 1 year after gastric bypass was 6.3%, in the Schauer et al study A1c was 6.4% after Roux-en-Y gastric bypass and in the Mingrone et al study A1c was 6.3% after laparoscopic gastric bypass or biopancreatic diversion. [53-55]

Very recently a systematic review and meta-analysis focused on medium term outcomes (five years) after banded Roux-en-Y gastric bypass showed that diabetes remission occurred in 82.2%. [56]

### **5.1. Lipid profile**

The outcomes of bariatric surgery are analyzed in a retrospective case-matched study com‐ paring medical treatment, duodenal switch, and laparoscopic adjustable gastric band to Rouxen-Y gastric bypass for treatment of obese type 2 diabetes. [51] At one year of follow-up the Roux-en-Y gastric bypass produced greater weight loss, A1c improvement, and higher diabetes medication score reduction than medical therapy and laparoscopic adjustable gastric bypass but duodenal switch produced greater reduction in A1c and diabetic medication score

Recently more and more evidences come from **randomized controlled trials**. These studies are difficult to be compared because of different inclusions criteria regarding the mean age, duration of diabetes, mean BMI and different primary endpoints and also lack of homogenous definition of diabetes remission. The first randomized controlled trial conducted on a small group compared conventional diabetes therapy consisting on weight loss by lifestyle changes versus laparoscopic adjustable gastric banding associated to diet on 60 obese patients (BMI >30 and <40) with recently diagnosed type 2 diabetes [52]. After two years of follow-up, remission of type 2 diabetes defined by fasting glucose level <126 mg/dl and glycated hemo‐ globin value <6.2% without glycemic therapy, was achieved by 73% in surgical group and by 13% in the conventional group. [52] As the authors recognized, this study has several limita‐ tions: relatively small number of patients, limited time of follow-up thus the results cannot be extrapolated for a longer period, lack of hard end points such as mortality and cardiovascular

A higher number of patients, 150 were included in Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently trial (STAMPEDE trial) and were randomly assigned to intensive medical therapy alone or intensive medical therapy plus either Roux-en-Y gastric bypass or sleeve gastrectomy. [53] These patients had a longer duration of diabetes, >8 years and mean BMI was 36 and glycated hemoglobin at baseline range from 8.9% to 9.5%. At 12 months of follow-up the target glycated hemoglobin level <6% was achieved by 12% in the intensive medical therapy alone group versus 42% in the gastric-bypass group and 37% in the sleeve-gastrectomy group, without significant differences between surgical groups. [53] Glycated hemoglobin and fasting plasma glucose improved significantly faster and at a great magnitude at three months in surgical groups compared with medical therapy group with a lower use of antidiabetic agents and this improvement was sustained over the entire followup period. [53] Type 2 diabetes mellitus control was significantly improved after both bariatric surgery procedures with a reduction of glycated hemoglobin by 2.9 percentage points. The average number of diabetes medications per patient per day increased in intensive medical therapy from 2.8 at baseline to 3 at one year and decreased in surgical groups from 2.6 (Rouxen-Y bypass group) and 2.4 (Sleeve gastrectomy group) to 0.3 and 0.9 respectively. [53] Insulin treatment at 12 months of follow-up was more prevalent among patients on intensive medical therapy group 38% versus gastric by-pass group 4% and sleeve-gastrectomy group 8%. [53] Not only glycemic control was improved secondly bariatric surgery but also HOMA-IR index, CRP level, lipid profile, with significantly decreased of triglycerides and increased of highdensity lipoprotein (HDL) cholesterol. The main limitation of this study, short duration of follow-up is overcome by another study with a follow-up period of two years, performed on

than Roux-en-Y gastric bypass. [51]

204 Treatment of Type 2 Diabetes

events [52].

Total cholesterol, LDL cholesterol and triglycerides were significantly lower in patients undergoing biliopancreatic diversion than among those receiving medical therapy but there were no significantly differences between medical therapy and gastric bypass. [54] The mean LDL cholesterol at follow-up was 83 mg/dl among patients who underwent gastric bypass versus 89 mg/dl in medical therapy groups. [54, 55] But triglycerides were significantly lower after one year in gastric bypass group versus medical group. [55] HDL cholesterol increased significantly in all three groups (medical therapy, gastric bypass and biliopancreatic diversion) but much more among patients undergoing gastric bypass. [54, 55]

#### **5.2. Blood pressure**

Systolic and diastolic blood pressures were significantly improved by gastric bypass and biliopancreatic diversion. [54, 55] No improvement of systolic and diastolic blood pressures was found in another study after Roux-en-Y gastric bypass or sleeve gastrectomy. [53]

Almost all studies showed that all metabolic improvements in the lifestyle-medical group were realized in the first 6 months of follow-up with subsequent decrease of the benefits by 12 months. In contrast improvement continues to increase in the bariatric surgery groups throughout the entire period of follow-up. [52-55]

The most recently published meta-analysis on observational and randomized clinical trial included 6131 patients: 3076 underwent bariatric surgery and 3055 underwent conventional therapy. [57] The mean age of patients included in this meta-analytic research was 47.8 years, ranging from 35.8 to 62.0 years. In the observational studies, the mean A1c in surgery groups was 7.6% versus 7.2% in conventional groups and at follow-up the mean A1c was 6.1% in surgery group versus 7% in conventional group. In the randomized trials, the mean A1c in surgery group was 8.9% versus 8.7% in conventional group and at follow-up the mean A1c was 6.1% in surgery group versus 7.6% in conventional group. In this meta-analysis the remission rate of type 2 diabetes ranged from 38% to 100% in surgery group versus 0% to 46.7% in conventional group. The odds of bariatric surgery patients reaching T2DM remission ranged from 9.8 to 15.8 times the odds of patients treated with conventional therapy. [57]

#### **5.3. Safety and adverse events**

The 30-day mortality associated with bariatric surgery is low, estimated at 0.1-0.3%, a rate similar to that for laparoscopic cholecystectomy. [58]

Biliopancreatic diversion and gastric by-pass are relatively safe and adverse events were rare including: incisional hernia, intestinal occlusion. [54, 55] Postoperative complications after gastric bypass consist on anastomotic and staple-line leaks (3.1%), wound infection (2.3%), pulmonary events (2.2%) and wound hematoma (1.7%) and late surgical complications consist on stricture, bleeding anastomotic ulcer, gastritis proximal pouch and small bowel obstruction but no mortality. [55, 59] Rare but often severe hypoglycemia form insulin hypersecretion could occur. [60] Patients in the gastric bypass group experienced 50% more serious and 55% more nonserious adverse events than did those in the lifestyle-medical group. [55] The most serious complication, anastomotic leakage, has decreased in incidence from 5% to 0.8%. [61, 62] A study performed by the US Agency for Healthcare Research and Quality reported a 21% decline in complications after bariatric surgery between 2002 and 2006. [63] The prevalence of postsurgical infections decreased by 58% and abdominal hernias, staple leakage, respiratory failure and pneumonia rates decreased by 29-50%.

Nutritional deficiencies such as: iron-deficiency anemia, hypoalbuminemia, vitamin B deficiency, vitamin D deficiency, osteopenia were more frequent in patients who underwent Roux-en-Y gastric bypass or biliopancreatic diversion despite monitoring of laboratory values and prescription of nutritional supplements. [54, 55, 60]

Some patients and surgery procedures factors related to higher risk have been identified until now. Patients' factors are: older age, increasing BMI, male gender, hypertension, obstructive sleep apnoea, high risk of pulmonary thromboembolism, limited physical mobility. Surgery procedures factors are: surgeon inexperience, low volume centre or surgeon performing surgery occasionally, morbidity and mortality increase with the complexity of the procedure, open compared with laparoscopic procedures, revisional surgery. [60, 64, 65] The presence of type 2 diabetes has not been found to be associated with increased risk for bariatric surgery.

#### **5.4. Conclusions**

Almost all studies showed that all metabolic improvements in the lifestyle-medical group were realized in the first 6 months of follow-up with subsequent decrease of the benefits by 12 months. In contrast improvement continues to increase in the bariatric surgery groups

The most recently published meta-analysis on observational and randomized clinical trial included 6131 patients: 3076 underwent bariatric surgery and 3055 underwent conventional therapy. [57] The mean age of patients included in this meta-analytic research was 47.8 years, ranging from 35.8 to 62.0 years. In the observational studies, the mean A1c in surgery groups was 7.6% versus 7.2% in conventional groups and at follow-up the mean A1c was 6.1% in surgery group versus 7% in conventional group. In the randomized trials, the mean A1c in surgery group was 8.9% versus 8.7% in conventional group and at follow-up the mean A1c was 6.1% in surgery group versus 7.6% in conventional group. In this meta-analysis the remission rate of type 2 diabetes ranged from 38% to 100% in surgery group versus 0% to 46.7% in conventional group. The odds of bariatric surgery patients reaching T2DM remission ranged

from 9.8 to 15.8 times the odds of patients treated with conventional therapy. [57]

The 30-day mortality associated with bariatric surgery is low, estimated at 0.1-0.3%, a rate

Biliopancreatic diversion and gastric by-pass are relatively safe and adverse events were rare including: incisional hernia, intestinal occlusion. [54, 55] Postoperative complications after gastric bypass consist on anastomotic and staple-line leaks (3.1%), wound infection (2.3%), pulmonary events (2.2%) and wound hematoma (1.7%) and late surgical complications consist on stricture, bleeding anastomotic ulcer, gastritis proximal pouch and small bowel obstruction but no mortality. [55, 59] Rare but often severe hypoglycemia form insulin hypersecretion could occur. [60] Patients in the gastric bypass group experienced 50% more serious and 55% more nonserious adverse events than did those in the lifestyle-medical group. [55] The most serious complication, anastomotic leakage, has decreased in incidence from 5% to 0.8%. [61, 62] A study performed by the US Agency for Healthcare Research and Quality reported a 21% decline in complications after bariatric surgery between 2002 and 2006. [63] The prevalence of postsurgical infections decreased by 58% and abdominal hernias, staple leakage, respiratory

Nutritional deficiencies such as: iron-deficiency anemia, hypoalbuminemia, vitamin B deficiency, vitamin D deficiency, osteopenia were more frequent in patients who underwent Roux-en-Y gastric bypass or biliopancreatic diversion despite monitoring of laboratory values

Some patients and surgery procedures factors related to higher risk have been identified until now. Patients' factors are: older age, increasing BMI, male gender, hypertension, obstructive sleep apnoea, high risk of pulmonary thromboembolism, limited physical mobility. Surgery procedures factors are: surgeon inexperience, low volume centre or surgeon performing surgery occasionally, morbidity and mortality increase with the complexity of the procedure,

throughout the entire period of follow-up. [52-55]

similar to that for laparoscopic cholecystectomy. [58]

failure and pneumonia rates decreased by 29-50%.

and prescription of nutritional supplements. [54, 55, 60]

**5.3. Safety and adverse events**

206 Treatment of Type 2 Diabetes

Up to date, all randomized controlled studies proving effects of bariatric surgery among obese type 2 diabetic subjects have been short-term and have been conducted on relatively small number of patients. Until now only the Swedish Obese Subjects (SOS) study provides evidence of cardiovascular benefits and prolonged improvement in glycemia but this is a non random‐ ized trial. [66, 67] Lager multicenter randomized controlled studies will be required in order to confirm these results. Furthermore is mandatory that studies designed for cardiovascular safety to be performed. More studies are needed especially studies that may provide a better prediction and duration of the remission of diabetes and long-term complications. The success of different bariatric surgery procedures suggests that they should not be seen as a last treatment. Such procedures have to be taken into account earlier in the treatment of type 2 diabetes obese patients.
