1. The Obesity/Diabetes Epidemic: Adiposopathy & ‘Obesity’- The New Disease! Weight Management in Obesity and DM: Emphasis on New Medical Therapies Stan Schwartz MD, FACP, FACE Private Practice, Ardmore Obesity Program Cardiometabolic Diabetes Center and Affiliate, Main Line Health System Emeritus, Clinical Associate Professor University of Pennsylvania Part 8 * *Part 8 of 9

2. Screen Patients for Diabetes Address Potential Causes of Weight Gain in Diabetes treatment Though drugs aimed at reducing insulin resistance and increasing beta cell function are logical pathophysiologically, ‘standard’ current pharmacologic therapy for Type 2 Diabetes increase weight (sulonylureas, glinides, insulin) BUT anything that reduces obesity (specifically visceral fat) will have the most significant benefit in preventing, treating and even reversing overt Diabetes. (even pioglitazone, GLP-1 RA’s, pramlintide, SGLT-2 inhibitors) Bariatric surgery, in many patients with Type 2 Diabetes has become a logical approach to prevent, treat, and even reverse, overt Diabetes AND reduce MORTALITY Diabetic Management of the Obese Patient

3. Potential Causes of Weight Gain With Treatment of Type 2 Diabetes Improved glycemic control with SU, INSULIN–reduce glycosuria, store food that shouldn’t be eating Fear of, or treatment for, hypoglycemia- eats extra Increased appetite –insulin/ SU Weight gain with insulin treatment –Correlates with insulin dose –Mean weight gain 3.2 - 4.4 kg per 1% reduction in A1C –About ⅔ adipose tissue and ⅓ lean body mass Westphal SA, et al. Insulin. 2007;2:31-36.

4. Weight Reduction Issues- Non -Insulin 0. In Metabolic Syndrome-consider Incretins/ SGLT-2 inh. 1. 3-4 non-insulin agents before consider insulin a. Not SU/GLINIDE b. AACE first Tier/ Second Tier Principle c. Beta cell- incretin/SGLT-2 Inh/ Pio d. Resistance- Pio/ metformin e. Other- bromocriptine-QR, colsevalam F EARLY TRIPLE THERAPY >>>>>>>>>>>>>>>>>>>>>>>>> 2. Incretins Before Pioglitazone- then don’t gain weight from pioglitazone 3. Ranolazine, SGLT-2 inh to minimize/prevent edema from pioglitazone 4.. GLP-1 RA’s and SGLT-2s have added wt. loss benefit 5. GLP-1 RA’s preferred over DPP-4 in ‘right patient’ 6. GLP-1 RA’s always before start Insulin, even a short trial-

5. 147 newly diagnosed T2DM initial combination therapy with metformin + pioglitazone + exenatide (Triple Therapy, n=71) or escalating dose of metformin followed by sequential addition of glipizide (5→20 mg/d) and then basal insulin to maintain A1c < 6.5% (Conventional Therapy, n= 76). Results: Triple Therapy, A1c 8.6 to 6.1% at 6 mo and remained stable at 6.1% at 24 Conventional Therapy, 6.1% at 6 mo and then increased to 6.6% at 24 mo (p < 0.01). More subjects in Conventional Arm failed to achieve the treatment A1c goal <6.5% (46 vs 22%, p<0.0001)., Triple Therapy subjects had a 13.6-fold lower rate of hypoglycemia compared to subjects receiving Conventional Therapy. Triple Therapy subjects had mean weight loss of 1.2 kg versus 3.6 kg weight gain (p=0.02) in subjects on Conventional Therapy. Conclusion: Antidiabetic therapy targeting the core metabolic defects (insulin resistance and beta cell dysfunction) responsible for hyperglycemia is more effective and safer than therapy simply aimed at lowering the plasma glucose conc without correcting the underlying pathophysiologic disturbances present in T2DM. Initial Triple Combination Therapy is Superior to Stepwise Add-On ConventionalTherapy in Newly Diagnosed T2DM; RALPH A. DEFRONZO,

6. Weight Reduction Issues- Non -Insulin 0. In Metabolic Syndrome-consider Incretins/ SGLT-2 inh. 1. 3-4 non-insulin agents before consider insulin a. Not SU/GLINIDE b. AACE first Tier/ Second Tier Principle c. Beta cell- incretin/SGLT-2 Inh/ Pio d. Resistance- Pio/ metformin e. Other- bromocriptine-QR, colsevalam F EARLY TRIPLE THERAPY 2. Incretins Before Pioglitazone- then don’t gain weight from pioglitazone 3. Ranolazine, SGLT-2 inh to minimize/prevent edema from pioglitazone 4.. GLP-1 RA’s and SGLT-2s have added wt. loss benefit >>>>>>>> 5. GLP-1 RA’s preferred over DPP-4 in ‘right patient’ 6. GLP-1 RA’s always before start Insulin, even a short trial-

7. SGLT-2 Inhibitor with Incretins