Diabetes surgery for the non-obese Dr John B Dixon, MBBS PhD Associate Professor Head of Obesity Research School of Primary Health Care Monash University, Melbourne, Australia NHMRC Senior research fellow Hypertension and Vascular – Obesity Research Baker Heart Research Institute Melbourne, Australia

Disclosures: Associate Professor John B Dixon Abbott Speakers Bureau & Educational Material Allergan Inc Consultant, Research Support Bariatric Advantage Consultant, Speakers Bureau Eli Lilly Speakers Bureau Merck Sharp and Dohme Speakers Bureau Nestle Australia Medical Advisory Board, Speakers Bureau, Research Support Novartis Australia Educational material ResMed Research Support Scientific Intake Consultant & Research Support SP Health Co Consultant Weight Watchers Speaker and Educational Material Valeant Pharmaceuticals Speaker and Educational Material

Diabetes surgery for BMI < 30 Why? Efficacy? Safety? How does it compare with medical therapy?

Why?

Relationship Between BMI and Risk of Type 2 Diabetes Age-Adjusted Relative Risk Body Mass Index (kg/m2) <23 24–24.9 25–26.9 27–28.9 33–34.9 25 50 75 100 1.0 2.9 4.3 5.0 8.1 15.8 27.6 40.3 54.0 93.2 <22 23–23.9 29–30.9 31–32.9 35+ 1.5 2.2 4.4 6.7 11.6 21.3 42.1 Men Women The risk of diabetes increases with increasing BMI values in men and women [1,2]. Moreover, the age-adjusted relative risk for diabetes begins to increase at BMI values that are considered normal for men (24 kg/m2) and women (22 kg/m2) based on mortality risk. The marked increase in the prevalence of obesity is an important contributor to the 25% increase in the prevalence of diabetes in the United States over the last 20 years [3]. Increases in abdominal fat mass, weight gain since young adulthood, and a sedentary lifestyle are additional obesity-related risk factors for diabetes [1,4,5]. 1. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995;122:481-486. 2. Chan JM, Rimm EB, Colditz GA, et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961-969. 3. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care 1998;21:518-524. 4. Ohlson LO, Larsson B, Svardsudd K, et al. The influence of body fat distribution on the incidence of diabetes mellitus. Diabetes 1985;34:1055-1058. 5. Helmrich SP, Ragland DR, Leung RW, Paffenbarger Jr RS. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-152. Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481.

Where is the increase in diabetes occurring? Gregg EW, Cheng YJ, Narayan KM, et al. Prev Med. 2007;45:348-52.

There is a burden of diabetes – But also real competition! 43% of those with diabetes are in this weight range There are a range of interventions Weight loss can produce important benefits in an intensive lifestyle program Look AHEAD Dietary interventions Metformin, SU, GLP-1 agonists, and DPP IV inhibitors and even insulin Quenexa ?

Efficacy

403 gastric cancer patients with T2DM underwent gastrectomy between May 2003 and September 2009. Information from medical records T2DM: resolution, improvement, same, and worse.

Results – mean 10% weigh loss

Factors influencing diabetes course

Factors influencing diabetes course

Multivariate analysis: Improvement was influenced most greatly by weight loss and weight gain Little happened with less than 10% weight loss

Authors conclusions

Studies of “Metabolic Surgery” BMI <35 Fried, M., G. Ribaric, et al. (2010). Obes Surg 20(6): 776-790.

Procedures Total 29 studies LII LDJB LRYGB LMGB Data on 675 patients BPD LAGB Total 29 studies Brazil 12 Italy 5 USA 2 Taiwan 2 Korea 2 Chile 2 Australia 1 Venezuela 1 Data on 675 patients Mean BMI change 29.95 – 24.83 17%

BMI < 35 – the whole review Remission HbA1c < 7% no medications

Prospective Study of RYGB for Type 2 DM in Asian Indians With BMI < 35 kg/m2 “Overweight” to “Obese” by Indian-specific WHO criteria Type 2 DM Confirmed with Abs, C-peptide, FHx Severe diabetes Mean duration: 9 years 80% on insulin (all others or oral DM meds) HbA1c: 10.1% Other features Dyslipidemia: 93% Hypertension: 60% Shah, S. S., J. S. Todkar, et al. (2009). Surg Obes Relat Dis.

RYGB in Asian Indians with body mass index <35: baseline and 9 months (n=15) Shah, S. S., J. S. Todkar, et al. (2009). Surg Obes Relat Dis.

RYGB in Asian Indians with body mass index <35 (n=15) There was significant and sustained reduction in HbA1c throughout the 9 months following RYGB (* after surgery). Shah, S. S., J. S. Todkar, et al. (2009). Surg Obes Relat Dis.

RYGB in Asian Indians with body mass index <35 (n=15) There was significant and sustained reduction in FBG throughout the 9 months following RYGB (* after surgery). Shah, S. S., J. S. Todkar, et al. (2009). Surg Obes Relat Dis. Source: Surgery for Obesity and Related Diseases (DOI:10.1016/j.soard.2009.08.009 ) Copyright © American Society for Metabolic and Bariatric Surgery Terms and Conditions

Did you calculate the weight loss? 20%

Gastric bypass – Taiwan A comparison of BMI <35 & >35 BMI<35 n=44 BMI > 35 n=157 Weight loss at 1–year 32% for all HbA1c <7% 76.5% of BMI<35 kg/m2 92.4% of BMI>35 (p=0.06) While there was a lower response rate in those with BMI <35 results still acceptable Lee, W. J., W. Wang, et al. (2008). J Gastrointest Surg 12(5): 945-952.

Mini-gastric bypass – Taiwan A comparison of BMI <35 & >35 BMI<30 Remission 62.5% cw 78% for >30

20 patients mini DS Duodenal part jejunal exclusion BMI 20-30 Excluded very poor control Selected only patients taking metformin, sulponylurea and glitizones included Ramos, A. C., M. P. Galvao Neto, et al. (2009). Obes Surg 19(3): 307-312.

Type 2 diabetes (n=20) Ramos, A. C., M. P. Galvao Neto, et al. (2009). Obes Surg 19(3): 307-312.

Laparoscopic Duodenal - jejunal bypass 20 diabetic patients underwent laparoscopic duodenal-jejunal exclusion. There was significant weight loss Mean 10% Only two patients were on oral medication after the sixth months - Only included those on oral hypoglycaemics There were no comments on complications in particular gastric emptying issues Studies with longer follow-up and a larger number of patients are necessary to better define the role of this new and promising procedure. Ramos AC, et al. Obes Surg. Mar 2009;19(3):307-312.

Lap Duodenal-Jejunal Bypass (n=7) 12 month prospective observational study Remission 1:7 Most reduced medications for diabetes HbA1c 9.4% to 8.5% FPG 209 to 154 mg/dl BMI 27.5 – 27.3 Authors recommend caution Ferzli, G. S., E. Dominique, et al. (2009). "Clinical improvement after duodenojejunal bypass for nonobese type 2 diabetes despite minimal improvement in glycemic homeostasis." World J Surg 33(5): 972-979.

Prospective randomized controlled trial of two versions of laparoscopic ileal interposition with sleeve gastrectomy Type 2 diabetic patients with BMI 21 – 34 Mean follow-up of 25 months HbA1c < 7 without medication in 90.9% of patients

Diverted Sleeve Gastrectomy Ileal Interposition – Sleeve Gastrectomy Ileal Interposition – Diverted Sleeve Gastrectomy ileum ileum

Weight Change = 26% Group comparisons with baseline - p<0.001

HbA1c before and after surgery * 8.6% 6.1% * p<0.001 vs corresponding group before surgery 82% of patients achieved optimal glycemic control, considered as HbA1c < 6.5%, without antidiabetic treatment DePaula AL, Vencio S, Mari A, Muscelli E, Ferranninni E. – Diabetologia 2009;52

Ileal interposition with sleeve gastrectomy At a 3-year follow-up there was a significant improvement in insulin sensitivity, insulin secretion and in the disposition index, as measured by a 3-hour OGTT study in type 2 diabetic patients who underwent laparoscopic ileal interposition with sleeve gastrectomy.

Biliopancreatic diversion BMI 25 -35 (n=30) Remission in 30% at 12 months Diabetes remission correlated positively with BMI at 12 months Initial BMI R2 = 0.25; P = 0.02 All patients with BMI ≥30 kg/m2 were in control at 12 months, 5 patients with BMI 25-30 HbA1c >7% Mean HbA1c 6.5% - Triglycerides went up Scopinaro, N., G. F. Adami, et al. (2011). Ann Surg 253(4): 699-703.

Biliopancreatic diversion BMI 25 -30 (n=15) 30-35 (n=15) 1 year changes BMI 30-35 HbA1c reduced from 9.5 – 5.9 Triglycerides fell and HDL-C unchanged BMI 25-30 HbA1c reduced from 9.1 – 6.9 Triglycerides were higher HDL-C lower It seem BMI may be quite important! Scopinaro, N., G. F. Adami, et al. (2011). Obes Surg 21(7): 880-888.

Beta cell defect V Insulin Resistance Hypothesis Age-Adjusted Relative Risk Body Mass Index (kg/m2) <23 24–24.9 25–26.9 27–28.9 33–34.9 25 50 75 100 1.0 2.9 4.3 5.0 8.1 15.8 27.6 40.3 54.0 93.2 <22 23–23.9 29–30.9 31–32.9 35+ 1.5 2.2 4.4 6.7 11.6 21.3 42.1 The risk of diabetes increases with increasing BMI values in men and women [1,2]. Moreover, the age-adjusted relative risk for diabetes begins to increase at BMI values that are considered normal for men (24 kg/m2) and women (22 kg/m2) based on mortality risk. The marked increase in the prevalence of obesity is an important contributor to the 25% increase in the prevalence of diabetes in the United States over the last 20 years [3]. Increases in abdominal fat mass, weight gain since young adulthood, and a sedentary lifestyle are additional obesity-related risk factors for diabetes [1,4,5]. 1. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995;122:481-486. 2. Chan JM, Rimm EB, Colditz GA, et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961-969. 3. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care 1998;21:518-524. 4. Ohlson LO, Larsson B, Svardsudd K, et al. The influence of body fat distribution on the incidence of diabetes mellitus. Diabetes 1985;34:1055-1058. 5. Helmrich SP, Ragland DR, Leung RW, Paffenbarger Jr RS. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-152.

Safety Safety data is limited and mixed It appears related to the complexity of the procedures Surgery is NOT likely to be safer than in class 1 obese patients No data on nutrition, quality of life, functional capacity, body composition, depression and psychological wellbeing

Gaede et al., NEJM, 2008;358:580-91

Steno multifactorial intervention 2 groups of 80 with type 2 diabetes and microalbuminuria Gaede et al., NEJM, 2008;358:580-91

Treatment of T2 diabetes Blood pressure Cholesterol, triglyceride Smoking Inactivity

Treatment of T2 diabetes Blood pressure Cholesterol, triglyceride Smoking Inactivity & Glycemic control

My Conclusions Evidence for surgery is very limited The best results come with the best weight loss Surgery is less effective at lower levels of BMI We will need properly conducted RCTs and benefits likely to be less substantial than in the severely obese Surgery specifically designed for GI effects without generating significant weight loss should proceed cautiously The competition at level is considerable and evidence WILL need to be of high quality and compelling