1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologist’s Eye Part 1

2. Duggal, Evidence-Based Medicine in Practice,, Int’l j. Clinical Practice,65:639-644,2011 Allan D. Sniderman, MD; Kevin J. LaChapelle, MD; Nikodem A. Rachon, MA; and Curt D. Furberg, MD, PhDMayo Clin Proc The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine October 2013;88(10):1108-1114 Trisha Greenhalgh et al, Evidence based medicine: a movement in crisis? BMJ 2014; 348 Lecture Based on Evidence-Based PRACTICE = = EBM=Evidence Based Medicine Has Led to Students/MDs who dont Think- Eg: if no evidence, continue doing same old dangerous therapy (SU); Specialists are abrogating their responsibility to evaluate and lead in use of new medications, processes of care = Evidence Based Practice EBM=Evidence Based Medicine Research Evidence Randomized, Prospective Publication Trials Critical Appraisal Patient-Based Experience Clinical expertise Expert Opinions Guidelines + +

3. Natural History of Type 2 Diabetes IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH pp>7.8

4. EPIGENITICSEPIGENITICS Pathogenic, β-CELL-CENTRIC Construct for All Diabetes Implications for Classification, Diagnosis, Prevention, Therapy, Research Inflammatory; Abnormal Immune Modulation β-Cell secretion/mass Polygenic- other Monogenic (HLA) Polygenic Monogenic - MODY − Mitochondrial Resistance (obesity) inflammatory adipokines Resistance-(obesity)- FFA Poor diet, inactivity Non Inflammatory Environmental Inflam. Triggers eg: viral,endocrine disruptors, food AGE’s, BIOME Gene EPIGENITICSEPIGENITICS endocrine disruptors, food AGE’s,BIOME Environmental Triggers PHENOTYPE

5. Why Bother to Treat Agressively?

6. Date of download: 4/17/2014 From: Trends in Prevalence and Control of Diabetes in the United States, 1988– 1994 and 1999–2010 Trends in Prevalence and Control of Diabetes in the United States Ann Intern Med. 2014;160(8):517-525. doi:10.7326/M13-2411 Prevalence of total confirmed diabetes and obesity. Data from U.S. adults aged ≥20 y in NHANES 1988–1994, 1999–2004, and 2005–2010. Total confirmed diabetes was defined as diagnosed diabetes or undiagnosed diabetes with diagnostic levels of both hemoglobin A 1c (≥6.5%) and fasting glucose (7.0 mmol/L [≥126 mg/dL]). Obesity was defined as body mass index ≥30 kg/m 2 ; 601 persons were missing body mass index data. Prevalence estimates for total confirmed diabetes and obesity were obtained using only the subsample of participants who attended the morning fasting session (7385 participants for 1988–1994, 5680 participants for 1999–2004, and 6719 participants for 2005–2010). The midpoint for obesity prevalence between 1988–1994 and 1999–2004 was calculated as the average of the prevalence of the 2 periods. NHANES = National Health and Nutrition Examination Survey. Figure Legend:

7. One third of adults with diabetes are undiagnosed  ~10% of US adults have diabetes/~20 million persons in 2005  Nearly one third dont know they have diabetes  26% of US adults have impaired fasting glucose (IFG)* *100–125 mg/dL Cowie CC et al. Diabetes Care. 2006;29:1263-8. NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov. Total: 35% of US adults with diabetes or IFG ~73.3 million persons

8. FBS>126 Ppg>200 New Hyperglycemia #223 (12%) Known Diabetes #495 (26%) Normo-Glycemia #1168 Mortality, total 16 3 1.7 Mortality, ICU 31 11 10 Mortality, non-ICU 10 1.7 0.8 LOS 9 5.5 4.5 ICU Admission 29 14 9 D/c Dispo. Home 56 74 84 Transition Care 20 15 10 Nursing Home 8 9 4 RISK OF UNRECOGNIZED HYPERGYCEMIA: Effect of Hyperglycemia on Mortality, LOS, ICU admission, D/C Disposition Umpierrez, JCEM 2002;87:978

9. Considering the Epidemic of Metabolic Syndrome, Prediabetes, Prevention Data, Undiagnosed Diabetes- ER Office and Pre-Admission IDENTIFICATION IS CRITICAL! Family history: whether parents or siblings have had diabetesFamily history: whether parents or siblings have had diabetes Obesity: especially with an increase in abdominal girthObesity: especially with an increase in abdominal girth High-risk ethnic group: African Americans, Hispanics, Native Americans, Asians, and Pacific IslandersHigh-risk ethnic group: African Americans, Hispanics, Native Americans, Asians, and Pacific Islanders Age: we’re looking at all ages, if patient seems at riskAge: we’re looking at all ages, if patient seems at risk Impaired fasting glucose or impaired glucose toleranceImpaired fasting glucose or impaired glucose tolerance Hypertension: blood pressure ≥ 140/90 mm Hg in adultsHypertension: blood pressure ≥ 140/90 mm Hg in adults High density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dLHigh density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dL Gestational diabetes or given birth to an infant weighing > 9 poundsGestational diabetes or given birth to an infant weighing > 9 pounds Pre-adm, pre-cath, pre-op, pre-CABGPre-adm, pre-cath, pre-op, pre-CABG FBS >100, ppg >140, POC HgA1c >6.0

10. 10 Hyperglycemia Spike (+variability) PPG Continuous A1C Acute toxicity Chronic toxicity Tissue lesion Diabetic complications Microvascular Macrovascular Retinopathy Nephropathy NeuropathyPVD MIStroke American Diabetes Association. At: http://www.diabetes.org/diabetes-statistics/complications.jsp. Brownlee M. Diabetes mellitus: theory and practice. Elsevier Science Publishing Co., Inc; 1990:279-291. Ceriello A. Diabetes. 2005;54:1-7. Hyperglycemia Leads to Complications: May Be Present Prior to Diagnosis Argument for Early Discovery Pre-diabetes, Early Treatment, Determine on Hospital Admission