Mae Sheikh-Ali, M.D. Assistant Professor of Medicine Division of Endocrinology University of Florida College of Medicine- Jacksonville

Transcription

1 Mae Sheikh-Ali, M.D. Assistant Professor of Medicine Division of Endocrinology University of Florida College of Medicine- Jacksonville

2 Pathogenesis of Diabetes Mellitus (DM) Criteria for the diagnosis of DM DM Complications Treatment Goals for DM DM Management -the new and the old Insulin therapy

3 Alpha Cells Glucagon Acts on liver to release glycogen Increases blood sugar Beta Cells Insulin Decreases blood sugar Colorado State University. Accessed December 3, Delta Cells Somatostatin Stops glucagon and growth hormone Decreases blood sugar

4 10% of diabetes is Type 1 1 Genetic link (chromosome 6HLA region) Presence of islet cell autoantibodies Autoimmune destruction of the beta cells 90% of diabetes is Type 2 2 Genetic predisposition Obesity Impairment of insulin secretion and defects in insulin action 1. Atkinson MA and Eisenbarth GS. Lancet. 2001;358: CDCP. December Atlanta, GA: US Dept. of Health and Human Services, CDCP, 2003.

5 Precipitating event Genetic predisposition Antibody formation Progressive loss of insulin release Beta Cell Mass Normal insulin release Glucose normal Overt diabetes C-peptide present No C-peptide present Time Atkinson MA and Eisenbarth GS. Lancet. 2001;358:

6 Obesity IGT Diabetes Uncontrolled Hyperglycemia Plasma Glucose Postmeal Glucose Fasting Glucose 120 mg/dl Relative Beta Cell Function 100% Insulin Resistance Insulin Secretion Years of Diabetes Bergenstal RM, et al. Endocrinology 4 th ed, 2000.

7 Beta Cell Function (%) IGT Postprandial Hyperglycemia Type 2 Phase 1 Type 2 Phase Years from Diagnosis Type 2 Phase 3 Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

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9 Eye Hyperglycemia Kidney Nerves Retinopathy Cataract Glaucoma Nephropathy Microalbuminuria Gross albuminuria Neuropathy Peripheral Autonomic Blindness Kidney failure Amputation Death and/or disability

10 Metabolic injury to large vessels Heart Brain Extremities Coronary artery disease Coronary syndrome MI CHF Cerebrovascular disease TIA CVA Cognitive impairment Peripheral vascular disease Ulceration Gangrene Amputation

11 Parameter Normal 1,2 Level ADA 3 Goal AACE/AC E 2 Goal FPG, mg/dl < <110 PPG, mg/dl <140 <180 <140 A1C, % 4 6 <7 a 6.5 a The goal for an individual patient is to achieve an A1C as close to normal (<6%) as possible without significant hypoglycemia. FPG=fasting plasma glucose; PPG=postprandial glucose; ADA=American Diabetes Association; AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology. 1. Adapted from Buse J et al. In: Williams Textbook of Endocrinology. 10th ed Permission requested. 2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1) ADA. Diabetes Care. 2007;30:S4 S41.

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13 HbA 1c (%) HbA 1c (%) DCCT EDIC (Type 1) 8 UKPDS (Type 2), Insulin Group Baseline yrs DCCT EDIC DCCT/EDIC Research Group. New Engl J Med. 2000; 342: Steffes et al. Diabetes (suppl. 2) 50: A Normal yrs UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:

14 Sulfonylurea Diet Time (years) Metformin Diet Time (years) UKPDS Group. Diabetes. 1995;44:

15 Lower A1c Preserve Beta cell function Lower CVD events

16 Efficacy in Lowering A1c Ability to Preserve Beta cell function Lower CVD events

17 Mechanism of action Typical Change in A1C Insulin Metformin Decrease hepatic gluconeogenesis Sulfonylurea Stimulate insulin secretion Glinides (Repaglinide, Nateglinide) TZDs (Rosiglitizoe, Pioglitizone) Alpha glycosidase Inhibitors (Acarbose, Miglitol) GLP 1 analogue Exenatide (byetta) Stimulate insulin secretion (short acting) Insulin sensitizer potentiate peripheral glucose uptake Inhibit digestion and absorption of carb in small intestine insulin, glucagon, gastric emptying, appetite 1.5 <1.0 <1.0 <1.0 DPP-4 Inhibiters (sitagliptine) Inhibit the degradation of GLP 1 <1.0 Amylin analogue Pramilintide ( Symlin) glucagon, gastric emptying, appetite <1.0

18 GLP-1 secreted upon the ingestion of food

19 GLP-1 (green) released into intestinal capillaries is immediately exposed to DPP-4 (red) 1 >50% of secreted GLP-1 is already degraded before it reaches the general circulation 1 >40% of circulating GLP-1 is already degraded before it reaches β-cells 2 Histochemistry by C. Ørskov, Panum Institute, Copenhagen. Copyright 1999, The Endocrine Society. 1. Hansen L, et al. Endocrinology. 1999;140: Deacon CF, et al. Am J Physiol. 1996;271(3 pt 1):E458-E464.

20 Mechanism of action Typical Change in A1C Insulin Metformin Decrease hepatic gluconeogenesis Sulfonylurea Stimulate insulin secretion Glinides (Repaglinide, Nateglinide) TZDs (Rosiglitizoe, Pioglitizone) Alpha glycosidase Inhibitors (Acarbose, Miglitol) GLP 1 analogue Exenatide (byetta) Stimulate insulin secretion (short acting) Insulin sensitizer potentiate peripheral glucose uptake Inhibit digestion and absorption of carb in small intestine insulin, glucagon, gastric emptying, appetite 1.5 <1.0 <1.0 <1.0 DPP-4 Inhibiters (sitagliptine) Inhibit the degradation of GLP 1 <1.0 Amylin analogue Pramilintide ( Symlin) glucagon, gastric emptying, appetite <1.0

21 Food Intake Gastric Emptying Insulin helps regulate glucose disappearance Postprandial Glucagon Amylin helps Amylin Insulin Gut regulate glucose appearance Pancreas GLP-1 21

22 Mechanism of action Typical Change in A1C Insulin Metformin Decrease hepatic gluconeogenesis Sulfonylurea Stimulate insulin secretion Glinides (Repaglinide, Nateglinide) TZDs (Rosiglitizoe, Pioglitizone) Alpha glycosidase Inhibitors (Acarbose, Miglitol) GLP 1 analogue Exenatide (byetta) Stimulate insulin secretion (short acting) Insulin sensitizer potentiate peripheral glucose uptake Inhibit digestion and absorption of carb in small intestine insulin, glucagon, gastric emptying, appetite 1.5 <1.0 <1.0 <1.0 DPP-4 Inhibiters (sitagliptine) Inhibit the degradation of GLP 1 <1.0 Amylin analogue Pramilintide ( Symlin) glucagon, gastric emptying, appetite <1.0

23 The newer drugs are less potent than insulin

24 In animal models some drug classes such as TZD and GLP1 preserve beta cell mass We do not have clinical data to demonstrate beta cell preservation in humans however studies with TZD have shown that they have better durability of efficacy compared to metformin and glyburide

25 Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma glucose of more than 180 mg per deciliter. Kahn et al. 355 (23): NEJM;2006

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27 The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive Trial)

28 Dormandy JA Lancet 366: ,2005.

29 The NEW ENGLAND JOURNAL of MEDICINE ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24 Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. CONCLUSIONS Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death that had borderline significance.

30 Just like the Vioxx patients who died without joint pain and The nifedipine patients who died with normal blood pressure and The Seldane patients who died without stuffy noses

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32 Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea Lifestyle + Metformin + Intensive insulin STEP 1 STEP 2 STEP 3 Tier 2: Less well validated core therapies Lifestyle + Metformin + Pioglitazone No hypoglycemia CHF Bone loss Lifestyle + Metformin + GLP-1 agonist No hypoglycemia Weight loss Nausea /vomiting Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Basal insulin

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34 Insulin (pmol/l) Glucagon (fmol/l) Glucose (mg/dl) 400 Postprandial hyperglycemia Type 2 Diabetes Normal Minutes Delayed and reduced Minutes Mitrakou A et al. Diabetes. 1990;39:

35 Glucose (mg/dl) Insulin ( U/mL) Type 2 on diet only Normal B L D B L D B=breakfast; L=lunch; D=dinner Time of day Polonsky KS et al. N Engl J Med. 1988;318:

36 Aspart ( Novolog), Glulisine, Lispro ( Humulog) 4 6 hours Plasma insulin levels Regular ( Novolin R, Humulin R) 6 8 hours NPH (Novolin N, Humulin N) hours Detemir (Levemir)14-24 Glargine ( Lantus) 24 hours Hours

37 Insulin Preparations Ultra-Rapid acting analogues Lispro Aspart Glulisine Short Acting Insulin (Human) Regular U-500 Intermediate-Acting (Human) NPH Intermediate-Acting Analogues Detemir Long Acting Analogues Glargine Action Profile (hours) Onset Peak Duration minutes minutes minutes minutes 1-3 hours hours hours hours 2-3 hours 6-12 hours 3-4 hours 3-4 hours 3-4 hours 6-8 hours hours 1.5 hours 4-10 hours hours 1-2 hours 6-8 hours hours hours No peak hours

38 pmol/l 400 Plasma Insulin mg/dl 200 Plasma Glucose Regular insulin Insulin lispro 300 Meal and insulin 150 Meal and insulin Heinemann L et al. Diabet Med. 1996;13: Minutes

39 U/mL B L D B=breakfast; L=lunch; D=dinner Time of day Polonsky KS et al. N Engl J Med. 1988;318:

40 U/mL NPH Regular B L D NPH Regular Normal pattern Time of day B=breakfast; L=lunch; D=dinner

41 U/mL Lispro, glulisine, or aspart B L D Glargine Normal pattern Time of day B=breakfast; L=lunch; D=dinner

42 U/mL Lispro, glulisine, or aspart B L D Detemir Normal pattern Time of day B=breakfast; L=lunch; D=dinner

43 Insulin Delivery: Spectrum of Options Durable and Disposable Options For accurate, consistent dose Current Standard Insulin Therapy Intensive Delivery System Therapy Intensive Insulin Pump Therapy

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