DIABETES RESEARCH A CLINICIAN S OVERVIEW

Transcription

1 DIABETES RESEARCH A CLINICIAN S OVERVIEW Alan B. Cortez, MD Chief, Pediatrics Pediatric Endocrinology Kaiser-Permanente Orange County January 21, 2012

2 Research Overview Biotechnology Treatment Pharmaceutical Treatment Biological Treatment/Cure Biological Prevention Nutritional Management Complication Prevention/Management Epidemiology

3 Biotechnology Insulin pump Glucose sensor Improvements in accuracy, predictive capabilities, and comfort; better understanding of how to use it Augmented insulin pump current sensors may be better at detecting decreasing bgs than increasing bgs. (Ward et al 2011 Diab Med) Artificial Pancreas

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5 Then. Now

6 Types of Artificial Pancreas Device Systems (APDS) CTR (Control to Range) Hypoglycemia Pump Shut off (Choudhary et al 2011) Hyperglycemia CTT (Control to Target) Insulin only vs Insulin/Glucagon Degree of Patient Control Pressing the mealtime button? Calibration with fingersticks Manual Override?

7 Full Closed Loop Vs. Hybrid Weinzimer et al. Diabetes Care May 2008 vol. 31 no

8 Distance Speed Acceleration Change in Accel Algorithm

9 Highlights from 64 Page FDA Guidelines- December 2011 Define types and subtypes of APDS Defines what data the FDA wants to see Delineates the 3 phase study approach- Early Feasibility, Transitional Clinical, Pivotal Clinical Define goals of rx- e.g., 0.4 reduction in A1c %, 30% reduction in hypoglycemia Define best populations to study- (e.g., doing well vs. not doing well; on pump/sensor vs. shots Proprietary Secrecy of Algorithms?

10 Pharmaceuticals- goals Safety- (don t cure the disease and kill the patient) Safety and Efficacy Maximized (Combinations of meds at lower doses that improve insulin secretion, enhance insulin action, increase glucose utilization, prevent glucose absorption, prevent complications, prevent/treat obesity) Prevention of islet cell apoptosis Islet Cell regeneration Physiologic and Convenient Insulin Delivery

11 Class of Diabetes Agents Sulfonylureas Biguanides Alpha-Glucosidase Inhibitors Thiazolidinediones Meglitinides DPP-4 Inhibitors GLP-1 Agonists Amylin Analogs Insulins/Insulin Analogs Combos/ Long Acting Preps Specific Agents glimepiride (Amaryl), glipizide (Glucotrol), glyburide (Micronase) Metformin (Glucophage) Glyset (miglitol), Precose (acarbose) Actos (pioglitzone), Avandia (rosiglitazone) Prandin (repaglinide), Starlix (nateglinide) Januvia (sitagliptin), Tradjenta (linaglptin), Onglyza (saxagliptin), Galvus (vildagliptin) Byetta (exanatide), Victoza (liraglutide) Symlin (Pramlinitide) Fast- Novolog (aspart), Humalog (lispro), Apidra (glulisine); Intermediate- NPH; Slow- Lantus (glargine), Levemir (detemir) Too numerous to mention!

12 Pharmaceuticals New Type 2 Products Juvisync (Sitagliptin and simvastatin) SGLT2 inhibitors (increase renal loss of glucose) Glucokinase agonists (lower set point for insulin release) GPR40 agonists- (enhance insulin release) 11 beta hydroxysteroid inhibitor (decrease counterregulatory hormones) Glucagon receptor antagonist (decrease gluconeogenesis and glycogenolysis) Glycogen inhibitors (decrease stored glucose)

13 State of the Art? Motivated Patient 1 st med: Metformin (unless thin?) 2 nd med: Insulin Secretagogue (sulfonylurea, DPP- 4 inhibitor, GLP-1 agonist) 3 rd/4th med(s): Basal Insulin (debate:?1 st med) or consider adding other med classes 5 th med: Bolus insulin

14 Pharmaceuticals- Insulin Making Insulin Superfast Zincless insulin (Biodel- Viaject/Linjeta) Hyaluronidase (Halozyme) Glucose-Responsive Insulin New Basal Insulin (Lilly- LY and LY , Novo- 40-hour degludec) Inhaled Insulin- (Afrezza) Pfizer and Lilly out Mannkind in (bought Exubera factory)

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18 Pharmaceuticals Making Insulin Superfast Zincless insulin (Biodel- Viaject/Linjeta) Hyaluronidase (Halozyme) Glucose-Responsive Insulin New Basal Insulin (Lilly- LY and LY , Novo- 40-hour degludec) Inhaled Insulin- (Afrezza) Pfizer and Lilly out Mannkind in (bought Exubera factory)

19 Glucose-Responsive Insulin- Smartinsulin Low Blood Glucose High Blood Glucose GRI GRI P B GRI L GRI H M Insulin Glucose

20 Pharmaceuticals Making Insulin Superfast Zincless insulin (Biodel- Viaject/Linjeta) Hyaluronidase (Halozyme) Glucose-Responsive Insulin New Basal Insulin (Lilly- LY and LY , Novo- 40-hour degludec) Inhaled Insulin- (Afrezza) Pfizer and Lilly out Mannkind in (bought Exubera factory)

21 New Inhaled Insulin is Smaller

22 Pharmaceuticals Obesity- last approval was Xenical in 1999 Cannabinoid-1 receptor blocker (rimonabant) Should be many candidate hormones to enhance or block the new hormones, but nothing so far. Phentermine/Topiramate (Qnexa) BuprorionSR/Naltrexone SR (Contrave)

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24 Biological- Beta Cell Replacement Strategies Extracted vs. Created Cultured vs. Fresh Natural vs. Engineered Beta Cells vs. Islet Cells Human Cells vs. Animals Cells Living vs. Cadaveric Single donor vs. Multiple Encapsulation vs. Immunosuppression Portal vs. Peripheral Liver vs. Pancreas Safety vs. Unintended consequences Edmonton Protocol (2000)- 2-3 pancreata, islet cell purification process, portal vein injection, less severe immunosuppression. MAJOR STEP FORWARD

25 Islet Cell Microencapsulation

26 Islet Cell Macoencapsulation

27 Islet Cell Regeneration Growth Factors (not eating Lettuce!) Genetic Engineering In vivo vs. ex vivo vs. in vitro RIP3.1 promotor- beta cell regeneration in streptozotocin- treated rats Chen et al 2010 Beta Cell vs Islet Cell

28 Diabetes Dogs

29 Prevention of Diabetes- Type 2 Type 2- Still #1: diet, exercise, weight loss Emerging Role of Bariatric Surgery- e.g., 2011 IDF paper metformin, acarbose, Xenical

30 Prevention of Diabetes- Type 1 Trialnet and other studies Prevention of Insulitis (in both genetically at risk and in everyone) Prevention of Progression from Insulitis to Diabetes Prevention of Progression form Honeymoon Period to Complete Type 1 DIabetes

31 BETA CELL MASS Loss of Beta Cell Function and Intervention in Type 1 Diabetes Prevent any damage Maternal (DHA) TRIGR (formula) TEDDY (enviro) Vaccine (GAD) NCS (enviro) GENETIC PREDISPOSITION Prevent early damage INSULITIS to BETA CELL INJURY Progressive loss of insulin function over ~ 5 yrs Anti-CD3 Anti-CD-20 Prevent Anti- CTLA-4 further Oral Insulin damage DiaPep277 Anti-IL1 beta MMZ/Anti-IL2 DIABETES APDS Insulin Accept Damage Islet Cell Replacement Islet Cell Regeneration Reverse Damage

32 Nutrition Management Healthy Nutrition Carbohydrate Counting (helpful unless you forget about healthy nutrition) Glycemic Index (Individual foods)- compares the amount of insulin secreted in response to a food normalized to a fixed amount of carbohydrate Food Insulin Index (Combinations of foods) Bao et al, 2011, Diabetes Care 34:2146

33 Prevention of Complications Excellent A1c levels over time (DCCT, DPP, European Databases) Role of other CVD/PVD risk factors- ACE, statins, ASA, obesity prevention Nephropathy- Role of SphK1, fibronectin- Lan et al, 2011 Mol Endocrin 25:2094 Foot Ulcers- Maggot therapy- 5% of cost- Marineau, ICAAC 2011 Neuropathy- aldose reductase inhibitors (epralrestat approved in Japan)

34 Retinopathy Retinopathy- oral PK-C inhibitor (ruboxistaurin), TyrK inhibitor eye drops (pazopanib) in animal studies 53% reduction in retinopathy in teens over past 20 years- Downie et al, Diabetes Care 34: year incidence declined from 33% to 6 % with more recent diagnosis Prevalence not changed because people with complications live longer

35 Epidemiology SEARCH (< 21 yr olds: 1 in 500 have type 1, 1 in 4000 get it per year; 50% of the incident year olds get type 2) National Children s Study TEDDY Looking for infectious trigger for Type 1 Looking for supergenes for Type 2

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