The Present and Future of Insulin Therapy in the Era of Pathophysiologic Treatment of T2DM: Marked Reduction of Insulin Use

Outline Value of Glycemic Control But do without Hypo Weight Gain Hypo topics – In general, SU, Insulin

Duggal, Evidence-Based Medicine in Practice,, Int’l j. Clinical Practice,65: ,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): 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 don’t 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 + +

Why Bother to Treat Agressively?

There’s Your ‘Market’

Date of download: 4/17/2014 From: Trends in Prevalence and Control of Diabetes in the United States, 1988–1994 and 1999–2010Trends in Prevalence and Control of Diabetes in the United States Ann Intern Med. 2014;160(8): doi: /M 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: EPIDEMIC

One third of adults with diabetes are undiagnosed ~10% of US adults have diabetes/~20 million persons in 2005 Nearly one third don’t 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: NIDDK. National Diabetes Statistics. Total: 35% of US adults with diabetes or IFG ~73.3 million persons

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

9 Hyperglycemia Spike (variability ) PPG Continuous A1C Acute toxicity Chronic toxicity Tissue lesion Diabetic complications Microvascular Macrovascular RetinopathyNephropathyNeuropathyPVD MIStroke American Diabetes Association. At: Brownlee M. Diabetes mellitus: theory and practice. Elsevier Science Publishing Co., Inc; 1990: Ceriello A. Diabetes. 2005;54:1-7. Hyperglycemia Leads to Complications BROWNLEE’s Unified Theory Often Present at Diagnosis

Trends in Age-Standardized Rates of Diabetes-Related Complications among U.S. Adults with and without Diagnosed Diabetes, 1990–2010. Gregg EW et al. N Engl J Med 2014;370:

Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials: BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications StudyMicrovascularMacrovascularMortality UGDP ↔↔↔ UKPDS ↓↓↔↓↔↓ DCCT/EDIC* ↓↓↔↓↔ ↔ ACCORD ↓↔ ↑ (unadj.), ↔ (adj.) ADVANCE ↓↔↔ VADT ↔↔↔ Initial Trial Long Term Follow-up ↑- likely due to hypoglycemia and weight gain

Hypoglycemia Outcomes VADT, ACCORD, ADVANCE

Consequences of Hypoglycemia Prolonged QT- intervals- Diabetologia 52:42,2009 – Can be of pronged duration IJCP Sup 129, 7/02 – Greater with higher catecholamine levels Europace 10,860 Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010 Associated with Arrhythmias Associated with Sudden Death Endocrine Practice 16,¾ 2010 Increased Variabilty- increases inflammation, ICU mortality Hirsch ADA2010

CV Risk of SU and Insulin Pharmacoepidemiology and Drug Safety. 2008;(17): So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC But adverse risk in ‘real world’ use- would not pass current FDA guidelines for CV risk with a new agent

Increased Mortality with SU Acute coronary syndrome in patients with diabetes mellitus: perspectives of an interventional cardiologist. Sanon S, Patel R, Eshelbrenner C, Sanon VP, Alhaddad M, Oliveros R, Pham SV, Chilton R. Am J Cardiol Nov 6;110(9 Suppl):13B-23B Endo 2012, abstract Fits FDA criteria for market withdrawal DOI: / Diabetes and Vascular Disease Research published online 4 January 2013 Thomas Forst, Markolf Hanefeld, Stephan Jacob, Guido Moeser, Gero Schwenk, Andreas Pfützner and Axel Haupt review and meta-analysis of observational studies

Complications CAN Be Reduced; MUST Avoid Hypoglycemia, Weight Gain 1.DCCT/EDIC and UKPDS- decreased Micro, Macrovascular disease 2. Confusion with VADT, ADVANCE, ACCORD Trials a. Older, longer duration DM, one third with CV disease b. Decreased micro, no benefit CV reduction, ACCORD increased Mortality c. we believe because undue hypoglycemia, weight gain 3. ADA says adjust HgA1c goal Higher if Older, longer duration DM, CV disease 4. I DISAGREE 5. We have 8 classes of drugs that have no undue risk hypoglycemia, weight gain a. so I’m Older, longer duration DM, CV disease -on 3 meds with no undue risk hypoglycemia, weight gain b. my HgA1c 5.4 !!- c. so I still aim for lowest without no undue risk hypoglycemia, weight gain