Therapy of Type 2 Diabetes Mellitus: UPDATE

1. Therapy of Type 2 Diabetes Mellitus: UPDATE Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines: Room For Improvement (Be HAPPY/ Avoid Burnout, While Caring for Patients with DM) Stan Schwartz MD, FACP, FACE Affiliate, Main Line Health System Clinical Associate Professor of Medicine, Emeritus, U of Pa. Part 6

2. STRESS (peri-op) DM STORY 1. Intensive in-hosp regimens resource intensive/ inc. hypo 2. Tried incretins- saw ~33% less patients needed insulin 3. steroids/ tacrolimus dec PDX-1 in b-cell, GLP-1 increase PDX-1 4. So incretins treat 2 stress hormones

3. Glp1 in major surgery in DMBenefit in Stress/ Steroid DM

4. IV GLP-1 (3.6 pmol/kg/min =400 pmol/L) For 12 hrs. after CABG in 20 Insulin Naive Type 2 Diabetic Patients • Insulin rescue if glucose > 140 mg% ( 7.77 mM) >3 hrs 0.005 u kg (GLP-1 group) vs 0.073u/kg (insulin group) ie: Greater than 10 x less insulin required over 12 hrs 2. Mean glucose 142 mg % (7.89 mM) (GLP-1 group), 146 mg % (8.12 mM) (insulin group) AUC glucose = both groups 3. No Hypoglycemia or Nausea, even with high dose 4. Less Pressors Mussig, j.amjcard.2008.06.029

5. Sub-cu Exenatide in Severely Burned Pediatric Patients: equal glycemic control, but: The use of exenatide in severely burned pediatric patients,Critical Care 2010, 14:R153,Gabriel A Mecott et al

6. Insulin Secretagogues: Sulfonylureas and “Glinides” • Safety and Efficacy -Decreases HbA1c approx1–2%(sfu, repaglinide)(0.5-1.0%,neteglanide) -Adverse events: Wt gain, sulfa allergy (sfu,rare), -cell apoptosis (sfu) Main risk = hypoglycemia , inc ischemia risk(~50% less w/repaglinide,75% less with neteglanide) Increase Cancer vs Metformin Abnormal ischemia pre-conditioning SO WHY USE SOMETHING THAT DESTROYS BETA-CELLS THAT YOU’D LIKE TO SAVE Davies MJ. Curr Med Res Opin. 2002;18(Suppl 1):s22-30.

7. Higher Mortality Is Associated With Greater Exposure to Sulfonylurea Monotherapy group Monotherapy group Deaths/1000 person-years Deaths/1000 person-years Hazard ratio Hazard ratio Adherence Daily Dose Poor (good) 1.55 1.34 1.33 49.0 (75.8) Glyburide (n = 4138) 1.10 1.09 0.98 Lower (higher) 1.32 1.29 1.29 37.7 (41.3) Metformin (n = 1537) 53.4 (70.2) Glyburide (n = 4138) 0 1 2 0.92 0.96 0.84 41.5 (37.6) Metformin (n = 1537) Unadjusted Adjusted for age, sex, chronic disease score (CDS), and nitrate use Adjusted for age, sex, CDS, nitrate use, physician visits, and hospital admissions 0 1 2 There was a greater risk of death associated with higher daily doses and better adherence for patients who used glyburide (HR = 1.3; 95% CI, 1.2-1.4), but not metformin (HR = 0.8; 95% CI, 0.7-1.1) A retrospective, inception cohort study conducted in 5795 new users of oral glucose-lowering medications - Insulin or combination therapy were excluded - Mean age: 66.3 years - Mean follow-up: 4.6 years - Main outcomes: all-cause mortality, death from acute ischemic event Simpson SH, et al. CMAJ. 2006;174:169-174.

8. CV Risk of SU and Insulin So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC But adverse risk in ‘real world’ use Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.

9. Sulfonylureas and Ischemic Pre-conditioning

10. MUST CONSIDER TOTAL COST- Incretin vs Sulfonylureas- not per/pill • ER Visits • Hospitalizations • Mortality • Under-recognized- hypoglycemic unawareness • Lifestyle Restrictions, diminished quality of life • Worry for Spouse, Friends, Co-workers • Fear of Hypoglycemic leads to inadequate Control • Severe Hypoglycemia Raises the Risk of Dementia • Increased cost of increased number SMBG testing And 2 Part-D insurers now ask for prior auth for GLYBURIDE, ? SUs And Given Apoptosis, death of beta-cells with SU, you’ll need expensive drugs anyway in 1-3 years- but now at disadvantage of having lost b-cell mass

11. Decrease b-cell demand- - dec CV outcomes, STOP- NIDDM • Decrease HbA1c 0.5–1% • Decrease PPG,TG • Delay DM Adverse events: flatulence,treat hypoglycemia with glucose