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Insulin Therapy in T2DM: Pathophysiologic Treatment

Explore the present and future of insulin therapy in the era of pathophysiologic treatment of T2DM, including the value of glycemic control, avoiding hypo and weight gain, and the need for evidence-based practice.

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Insulin Therapy in T2DM: Pathophysiologic Treatment

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

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

  3. Lecture Based on Evidence -Based PRACTICE = 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 EBM=Evidence Based Medicine Patient-Based Experience Clinical expertise Expert Opinions Guidelines Research Evidence Randomized, Prospective Publication Trials Critical Appraisal + + = Evidence Based Practice EBM=Evidence Based Medicine 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

  4. Why Bother to Treat Agressively?

  5. There’s Your ‘Market’

  6. EPIDEMIC 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 Figure Legend: 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 A1c (≥6.5%) and fasting glucose (7.0 mmol/L [≥126 mg/dL]). Obesity was defined as body mass index ≥30 kg/m2; 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. Ann Intern Med. 2014;160(8):517-525. doi:10.7326/M13-2411 Date of download: 4/17/2014

  7. 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)* • Total: 35% of US adults with diabetes or IFG • ~73.3 million persons Cowie CC et al. Diabetes Care. 2006;29:1263-8. NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov. *100–125 mg/dL

  8. 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 diabetes • Obesity: especially with an increase in abdominal girth • High-risk ethnic group: African Americans, Hispanics,Native Americans, Asians, and Pacific Islanders • Age: we’re looking at all ages, if patient seems at risk • Impaired fasting glucose or impaired glucose tolerance • Hypertension: blood pressure ≥ 140/90 mm Hg in adults • High density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dL • Gestational diabetes or given birth to an infant weighing > 9 pounds • Pre-adm , pre-cath, pre-op , pre-CABG • FBS >100, ppg >140, POC HgA1c >6.0

  9. Hyperglycemia Leads to Complications Hyperglycemia Spike (variability) Continuous BROWNLEE’s Unified Theory PPG A1C Chronic toxicity Acute toxicity Tissue lesion Diabetic complications Microvascular Macrovascular MI Stroke Retinopathy Nephropathy Neuropathy PVD Often Present at Diagnosis 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. 9

  10. 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;370:1514-1523

  11. 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 Initial Trial Long Term Follow-up ↑- likely due to hypoglycemia and weight gain

  12. Hypoglycemia Outcomes VADT, ACCORD, ADVANCE

  13. 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

  14. 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- would not pass current FDAguidelines for CV risk with a new agent Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.

  15. Increased Mortality with SU Endo 2012, abstract Fits FDA criteria for market withdrawal DOI: 10.1177/1479164112465442 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 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. 2012 Nov 6;110(9 Suppl):13B-23B

  16. Complications CAN Be Reduced; MUST Avoid Hypoglycemia, Weight Gain • 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

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