Treating Type 2 Diabetes by Treating Obesity. Vijaya Surampudi, MD, MS Assistant Professor of Medicine Center for Human Nutrition

Treating Type 2 Diabetes by Treating Obesity Vijaya Surampudi, MD, MS Assistant Professor of Medicine Center for Human Nutrition 2

Center Stage Obesity is currently an epidemic in the United States, with almost 70% of Americans overweight and one of three obese.

Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults Obesity (BMI 30 kg/m 2 ) 1994 2000 2015 Diabetes No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0% 1994 2000 2015 No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% CDC s Division of Diabetes Translation. United States Surveillance System available at http://www.cdc.gov/diabetes/data

Obesity Management was added a few years ago and remained in the Standard of Medical Care in Diabetes 2018. 5

The Natural History of Type 2 Diabetes Saisho Y. Postprandial C-Peptide to Glucose Ratio as a Marker of β Cell Function: Implication for the Management of Type 2 Diabetes. Int J Mol Sci. 2016 May 17;17(5). 6

Insulin Resistance Visceral Fat Weight Loss Insulin Sensitivity Glucose Toxicity Lipotoxicity Inflammation Low Carb Exercise VLCD Exercise Insulin Sensitivity Insulin Sensitivity Insulin Sensitivity 7

Overweight/Obesity Treatment w/ T2DM Body Mass Index Category (kg/m 2 ) Treatment Diet, physical activity & behavioral therapy 23.0* or 25.0-26.9 27.0-29.9 27.5* or 30.0-34.9 35.0-39.9 40 Pharmacotherapy Metabolic surgery * Asian-American individuals Treatment may be indicated for selected, motivated patients. American Diabetes Association Standards of Medical Care in Diabetes. Obesity management for the treatment of type 2 diabetes. Diabetes Care 2018; 41 (Suppl. 1): S65-S72

Evidence for Lifestyle Change There is overwhelming evidence that modest sustained weight loss, for example, current target of 5 10%, prevents the onset of most new T2DM in people with pre-diabetes. It improves all aspects of diabetes control: Hyperglycemia Blood pressure Lipids Reductions in drug doses for medications used to treat hypertension, diabetes and dyslipidemia. 9

Nutrition Recommendations for Diabetes Mellitus From Late 19 th Century 1890s: Rice, oatmeal, potato, legume, or porridge diets 1979: American Diabetes Association Carb: 50-60% Protein: 12-20% Fat: <10% as saturated fat 43% Carb 18% Protein 39% Fat <1000 cal 1927: Joslin's "weighed diets 1900-1920 s:allen's "starvation" diet Low Carb High Fat Low cal 22% Carb 16% Protein 62% Fat ~1500-1800 cal 1986: American Diabetes Association Carb: 55-65% Protein: 0.8 g/kg Fat: Total fat <30% 10

Number and Percentage of U.S. Population with Diagnosed Diabetes, 1958-2015 CDC s Division of Diabetes Translation. United States Diabetes Surveillance System available at http://www.cdc.gov/diabetes/data

Major Randomized Control Trials that looked at Intensive Lifestyle Interventions Diabetes Prevention Program (DPP) Look AHEAD CALERIE 12

In the 2.8 years of the Diabetes Prevention Program (DPP) randomized clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. They investigated the persistence of these effects in the long term. All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years 13

10-year follow-up of Diabetes Incidence and Weight Loss in the Diabetes Prevention Program Outcomes Study 14

10-year follow-up of Diabetes Incidence and Weight Loss in the Diabetes Prevention Program Outcomes Study 15

Major Randomized Control Trials that looked at Intensive Lifestyle Interventions Diabetes Prevention Program (DPP) Look AHEAD CALERIE 20

In 16 study centers in the United States, they randomly assigned 5145 overweight or obese patients with type 2 diabetes to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262). 21

From: Association of an Intensive Lifestyle Intervention With Remission of Type 2 Diabetes JAMA. 2012;308(23):2489-2496. doi:10.1001/jama.2012.67929 Date of download: 10/5/2017 Copyright 2012 American Medical Association. All rights reserved.

N Engl J Med. 2014 May 8;370(19):1866 In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). 23

Changes in Weight, Physical Fitness, Waist Circumference, and Glycated Hemoglobin Levels during 10 Years of Follow-up.

Major Randomized Control Trials that looked at Intensive Lifestyle Interventions Diabetes Prevention Program (DPP) Look AHEAD CALERIE 25

To determine CR s feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese (BMI 22-28) humans aged 21 51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. 26

Changes in Weight during a 2 Years of Follow-up. 27

Changes in Cholesterol, Triglycerides, Insulin Resistance and Blood Pressure during a 2 Years of Follow-up. 28

Recommendations: Metabolic Surgery Metabolic surgery should be recommended to treat T2DM for all appropriate surgical candidates with BMIs > 40 (37.5*) and those with BMIs 35.0-39.9 (32.5-37.4*) when hyperglycemia is inadequately controlled despite lifestyle & optimal medical therapy. A American Diabetes Association Standards of Medical Care in Diabetes. Obesity management for the treatment of type 2 diabetes. Diabetes Care 2018; 41 (Suppl. 1): S65-S72

Types of Surgeries

Original Article Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects Lena M.S. Carlsson, M.D., Ph.D., Markku Peltonen, Ph.D., Sofie Ahlin, M.D., Åsa Anveden, M.D., Claude Bouchard, Ph.D., Björn Carlsson, M.D., Ph.D., Peter Jacobson, M.D., Ph.D., Hans Lönroth, M.D., Ph.D., Cristina Maglio, M.D., Ingmar Näslund, M.D., Ph.D., Carlo Pirazzi, M.D., Stefano Romeo, M.D., Ph.D., Kajsa Sjöholm, Ph.D., Elisabeth Sjöström, M.D., Hans Wedel, Ph.D., Per-Arne Svensson, Ph.D., and Lars Sjöström, M.D., Ph.D. N Engl J Med Volume 367(8):695-704 August 23, 2012

Study Design The SOS study is a nonrandomized, prospective, controlled intervention trial comparing the long-term effects of bariatric surgery with the effects of usual care. All the patients in the surgery and control groups entered this study with the intention of losing weight. In the bariatric-surgery group, 311 participants underwent banding, 1140 vertical banded gastroplasty, and 207 a gastric bypass procedure. Patients in the control group received the customary treatment for obesity at their primary health care centers. 34

The Swedish Obesity Study (SOS) 20 year follow Up Data

The Swedish Obesity Study (SOS)

Three-thousand four-hundred and eighty-five obese individuals receiving bariatric surgery or conventional treatment were grouped into four baseline BMI categories (<35, 35 40, 40 45 or 45 kg/m2) and five weight-change categories according to their BMI at 2 years. The incidence and remission of diabetes at 2 years was assessed. 37

T2D Incidence 38

T2D Remission 39

Diabetes Care. 2016 Jul;39(7):1101-7 An observational cohort of obese participants was studied. Of 2,458 obese participants enrolled, 1,868 (76%) had complete data to assess diabetes status at both baseline and at least one follow-up visit. Of these, 627 participants (34%) were classified with diabetes: 466 underwent RYGBP and 140 underwent LAGB. 40

3 Years Follow up Data

They assessed outcomes 5 years after 150 patients who had type 2 diabetes and a bodymass index of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy

Schauer PR et al. N Engl J Med 2017;376:641-651

Potential Mechanisms of Diabetes Remission after Bariatric Surgery 45

GI Tract Largest Endocrine Organ

Hormonal change during bariatric surgery Singh AK, Singh R, Kota SK. Bariatric surgery and diabetes remission: Who would have thought it? Indian Journal of Endocrinology and Metabolism. 2015;19(5):563-576.

Singh AK, Singh R, Kota SK. Bariatric surgery and diabetes remission: Who would have thought it? Indian Journal of Endocrinology and Metabolism. 2015;19(5):563-576. 48

Revisiting Diet 49

Recommendations: VLCD Small studies have demonstrated that in obese patients with type 2 diabetes more extreme dietary energy restriction with very-low-calorie diets can reduce A1C to <6.5% (48 mmol/mol) and fasting glucose to <126 mg/dl (7.0 mmol/l) in the absence of pharmacologic therapy or ongoing procedures. 51

VLCD Very Low Calorie Diet (VLCD) <800 kcal per day Low Calorie Diet (LCD) >800 kcal per day A VLCD may be used for a short time to promote quick weight loss among some people who are considered to be obese. 52

T2D duration of 0.5 23 years (n = 30) followed a VLCD for 8 weeks. All oral agents or insulins were stopped Following a stepped return to isocaloric diet, a structured, individualized program of weight maintenance 53

Results 54

Diabetes 62:3027 3032, 2013 They studied eleven subjects who underwent RYGB and fourteen subjects mean-matched for BMI, HbA1c, and diabetes duration who were admitted to our inpatient research unit and given a very low calorie diet (VLCD) of 500 kcal/day with a macronutrient content similar to that consumed by patients after RYGB. Frequently sampled intravenous glucose tolerance tests were performed before and after interventions.

Beta Cell Function

Very Low and Low Calorie Diets Are Effective to Reverse Pre-Diabetes in Ambulatory Care Settings Vijaya Surampudi MD, MS, Xinkai Zhou MS, Chi-Hong Tseng PhD, Zhaoping Li MD, PhD University of California Los Angeles

Subjects Total Subjects N=4634 N =2572 Baseline analysis Excluded due to Inclusion/Exclusion: N = 2062 Normal Subjects N=1396 IFG Subjects N=1176 Presented at Endocrine Society 2018 Unpublished Data

Percentage Results: Glucose Percentage of patients with normalization of blood glucose <100 mg/dl in relation to amount of weight lost. 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% Normalization of Blood Glucose at 3 months <5/<2.2 (5-10)/(2.2-4.5) (10-15)/(4.5-6.8) >=15/>=6.8 Weight Loss (lbs/kgs) Presented at Endocrine Society 2018 Unpublished Data

Conclusion There is overwhelming evidence that modest sustained weight loss, for example, current target of 5 10%, prevents the onset of most new T2DM in people with pre-diabetes. Bariatric surgery is now a suggestion for obese people with T2DM. Surgery carries immediate and long-term risks, and is not acceptable to all people. The metabolic benefits of bariatric surgery have been observed by negative energy balance alone, using a low-energy liquid-formula diets. More studies need to be done but the evidence is growing 61