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Presentation on theme: "DIABETES MANAGEMENT 2006: INTEGRATING NEW MEDICINES AND NEW DEVICES"— Presentation transcript:

Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Declaration of full disclosure: No conflict of interest

2 Diabetes Mellitus in the US: Health Impact of the Disease
6th leading cause of death Renal failure* Life expectancy -5 to 10 yr Blindness* Diabetes Cardiovascular disease 2x to 4x Nerve damage in 60% to 70% of patients Amputation* *Diabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputations

3 Diabetes Mellitus: U.S. Impact
16.7 Million (8.3%) IFG 12.3 Million (6.3%) ~1 Million Type 1 ~16 Million Type 2 TOTAL: 29 Million (14.4%) 1/3 Undiagnosed (4.9 Million) 2/3 Diagnosed

4 Screening for Diabetes
ADA: >45, especially if BMI >25. <45 if overweight and have risk factor for DM (inactive, FH, high risk ethnicity, baby >9 lb, HTN, low HDL or high TG, PCOS, vascular disease). Screen with FPG or 2-h OGTT Diabetes Care, 2006 USPSTF: Insufficient evidence to recommend for or against. However, recommend screening in adults with hypertension and lipid disorders Ann Intern Med, 2003

5 Diagnosis of Diabetes Two measures of any of the following:
Random glucose: 200 mg/dl with symptoms (poly’s, weight loss) Fasting glucose: 126 mg/dl 2-hr glucose: 200 mg/dl during OGTT Diabetes Care 2006

6 HbA1C for Screening ? HbA1c 2SD above mean has sensitivity of 66 % and specificity of 98 % and compares favorably to FPG Different nondiabetic reference ranges due to different glycated hemoglobin fractions Precision and accuracy may not be sufficient in all labs Affected by hemoglobinopathies, anemia, transfusions, uremia, pregnancy

7 Diagnosis of Pre-Diabetes
Two measures of any of the following: Fasting glucose mg/dl 2-hr glucose mg/dl during OGTT

8 DPP: % Developing DM After 3 Years
% developing Diabetes

9 Prevention of Type 2 DM: RCTs
Trial Description Results (RR) Da Qing1 Diet &/or exercise 31 to 46% Finnish Prevention Study (FPS)2 Intensive lifestyle 58 % Diabetes Prevention Meformin % Program (DPP)3 Lifestyle 58 % STOP- NIDDM4 Acarbose 25 % TRIPOD5 Troglitazone %

10 Recommendations for Adults
Glycemic Control A1C: <7.0 Preprandial: mg/dl Postprandial: <180 mg/dl Blood Pressure: <130/80 mmHg Lipids LDL: <100 mg/dl TG: <150 mg/dl HDL: >40 mg/dl ADA Diabetes Care 2006

11 Treatment of Type 2 Diabetes
Step 1: Lifestyle Changes Step 2: Oral Monotherapy Step 3: Combination Oral Therapy Step 4: Oral Therapy plus Insulin Step 5: Insulin Alone Step 6: Insulin plus Thiazolidinedione/Metformin Target metabolic values need to be individualized

12 Attaining Glycemic Goals Using Monotherapy in Obese Patients With Type 2 Diabetes
Turner RC et al. JAMA. 1999;281:

13 Treatment of Type 2 Diabetes Improved Glycemic Control
Delay digestion of carbohydrates Acarbose/ Miglitol SFUs/Insulin Metformin Decrease Hepatic Glucose Output Improved Glycemic Control Increase Insulin Secretion Decrease insulin resistance Thiazolidinediones

14 Generic Oral Hypoglycemic Slide
Change from Drug A to B, C, or D Add Drug A to B, or B to A HgA1c Add Drug C Add Drug D Time

15 Adding Instead of Switching
Continue glyburide Switch to metformin 1 Glyburide+ metformin +0.2% 0.4% * * * * 1 Change in Mean HbA1c (%) 1.7% 2 3 9 13 17 21 25 29 Treatment (wk) DeFronzo, et al. N Engl J Med. 1995;333: , 5-2

16 Oral Agent “Failure” Why does this occur?
Changing HbA1c goals Compliance, side effects Wrong diagnosis (LADA--latent autoimmune diabetes in adults 10%) Stress, diabetogenic medications Natural progression of the disease

17 Natural History of Type 2 Diabetes
Obesity IFG* Diabetes Uncontrolled hyperglycemia 350 Post-meal Glucose 300 250 Glucose (mg/dL) 200 Fasting Glucose 150 100 50 250 200 Insulin Resistance Relative Function (%) 150 100 Insulin Level` 50 Beta-cell failure -10 -5 5 10 15 20 25 30 Years of Diabetes *IFG = impaired fasting glucose

18 Natural History of Type 2 Diabetes
Thiazolidinedione - Biguanide Lifestyle Insulin SU 350 Post-meal Glucose 300 Glucose (mg/dL) 250 Fasting Glucose 200 150 100 50 250 200 Relative Function (%) Insulin Resistance 150 100 Insulin Level 50 Beta-cell failure -10 -5 5 10 15 20 25 30 Years of Diabetes

19 Insulin Plus Oral Agents
Introduction of insulin Bedtime Intermediate/Long-acting insulins NPH, UL, glargine 10 units Self-monitoring of blood glucose (hypoglycemia education) Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)

20 When to go to > 1 shot per day
HgA1c >7 Glucose in AM at goal but g lucose before dinner >140 Options Add premeal lispro/aspart Add bid premixed insulin – 70/30, 75/25 Questions Continue metformin ? Sulfonylurea, ? Thiazolidinedione

21 Function of Insulin in Regimens
Meal coverage (carbohydrates) Basal insulin Correction of high blood sugar

22 More Options Insulins Insulin Lispro (Humalog®) ‘96
Insulin Aspart (Novolog®) 9/00 Humalog ® Mix 75/25 1/00 Insulin Glargine (Lantus®) 4/00 Novolog ® Mix 70/30 5/02 Insulin Glulisine (Apidra®) 4/04 Insulin Detemir (Levemir®) 6/05 Insulin delivery devices and glucose meters

23 Insulin Pharmacokinetics
On July 6, 2005 Lilly announced Lente and Ultralente will no longer be available in 2006.

24 Plasma Insulin (pmol/L) Plasma Insulin (pmol/L)
Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles 400 glulisine 500 Aspart Lispro 450 350 400 300 350 250 300 Plasma Insulin (pmol/L) 200 250 Plasma Insulin (pmol/L) Regular 200 150 Human 150 100 Regular 100 Human 50 50 30 60 90 120 150 180 210 240 50 100 150 200 250 300 Time (min) Time (min) Meal SC injection Meal SC injection Heinemann, et al. Diabet Med. 1996;13: ; Mudaliar, et al. Diabetes Care. 1999;22: 6-28

25 Rapid-Acting Insulins
Advantages • Flexibility--given immediately before or after meals • Postprandial control-better match with glucose peak • Limited duration so less overlap with subsequent injections Disadvantages • Caution with adequate CHO intake (if < than predicted, susceptible to hypoglycemia • Cost/insurance coverage

26 Activity Profile in Type 1 Diabetes
Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015 (Hourly Mean Values) 6 (mg/kg/min) 5 Insulin Glargine 4 NPH insulin 3 Glucose 2 Utilization Rate 1 10 30 20 Time (h) after sc injection = End of observation period

27 Type 2 Diabetes: Unanswered Questions
When should insulin be started? What insulin should you use in Type 2? What insulin regimen is best? Which, if any, oral agents should be continued?

28 Insulin tactics Minimize weight gain – metformin
Minimize risk of hypoglycemia – insulin analogs, optimize self management skills Minimize insulin resistance – thiazolidinediones and metformin Use oral agents to limit number of injections

29 More Options Incretin mimetics Exenatide (Byetta ®) 4/05
Amylinomimetics (amylin analog) Pramlintide (Symlin ®) 3/05

30 Incretins in Type 2 DM Gut hormones released postprandially
Oral glucose elicits greater insulin response than IV glucose; “incretin effect” accounts for 50-70% of insulin response to oral glucose 2 main gut incretins Glucose-dependent insulinotropic polypeptide (GIP) Released by K cells in duodenum Glucagon-like peptide-1 (GLP-1) Released by L cells in small intestines Levels are diminished in type 2 DM post-meal

31 Incretins in Type 2 DM (cont)
Rapidly degraded by dipeptidyl peptidase IV (DPP-IV) GLP-1 analogs; “incretin mimetics” Liraglutide (free fatty acid added to bind to albumin; injected daily) Exenatide DPP-IV inhibitors (oral)

32 Actions of GLP-1 Insulin secretion (Insulinotropic effects)
Potentiates glucose-induced insulin secretion Enhances all steps of insulin biosynthesis Upregulates insulin gene expression Upregulates genes needed for beta-cell function ( Stimulates beta cell proliferation Promotes differentiation of beta cells from progenitor cells Inhibits glucagon secretion (Glucostatic effect) Slows gastric emptying Inhibits appetite and food intake

33 Exenatide (Byetta) Synthetic Exendin-4, or exenatide Exendin-4 originally isolated from Gila monster’s (Heloderma suspectum) saliva; lizard in Arizona Analog of GLP-1 39 amino acid peptide >50% overlap with human GLP-1 Resistant to DPP-IV degradation Similar binding affinity at GLP-1 receptors

34 Exenatide (Byetta) Indications: adults with type 2 DM who are taking metformin, sulfonylurea or combination Peak concentration post injection achieved in 2.1 hr (injected SQ twice daily within 60 minutes of meal) Metabolized primarily by kidneys Not recommended in Clcr <30 ml/min OK in hepatic impairment

35 Restores first-phase insulin response Slows gastric emptying
Exenatide: BG Effects Lowers post-prandial BG Restores first-phase insulin response Slows gastric emptying Lowers post-prandial glucagon ( hepatic glucose output)  food intake Lowers A1C

36 Clinical Data: Exenatide
3 large, 30 week clinical trials (randomized, double-blind, placebo-controlled) in patients with type 2 DM On SFU: Buse et al. Diabetes Care. 2004;27: On SFU & metformin: Kendall DM et al. Diabetes Care. 2005;28: On metformin: DeFronzo RA et al. Diabetes Care. 2005;28: Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID ITT 483 480 Age (y) 55 BMI 34 33 A1C 8.5 8.4 Duration of DM 8 7

37 A1C (%) Effect (change from baseline)
Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID MET 0.1 -0.4 -0.8 SFU -0.5 -0.9 MET+SFU 0.2 -0.6 Changes in A1C from baseline vs placebo statistically significant Effect on FBG less pronounced:  6-9 mg/dl (5 mcg dose); 10 mg/dl (10 mcg dose) PPG 60% (5 mcg dose) & 90% (10 mcg dose)

38 Weight (change from baseline) & Hypoglycemia
Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID Weight (kg) -1.4 -3.1 -4.2 Hypoglycemia (%) MET SFU MET + SFU 5.3 3.3 1.26 4.5 14.4 19.2 35.7 27.8 Open-label extension study to 90 weeks: persistence in weight loss and A1C

39 Exenatide Dosing Start 5 mcg SQ BID before morning and evening meal When added to SFU, lower dose of SFU After 1 month, can increase to 10 mcg SQ BID Available in prefilled pen Must be continuously stored refrigerated at 36-46°F For oral medications dependent on threshold concentrations or rapid onset, take them 1 hour before

40 Side Effects GI Nausea (44% vs 18% with placebo); incidence lessens over time; 3% dropout rate due to nausea Vomiting (13% vs 4%) Diarrhea (13% vs 6%) Headache (9% vs 6%) Hypoglycemia (see previous slide)

41 New Options for Insulin Delivery
Ideal Insulin Pen: Ease of priming, loading cartridge Sturdy/reliable Change dose without wasting insulin Easy to read numbers Flexibility in dosing range (wide range, 1 vs 2-unit increments) Not costly

42 Durable Insulin Pens Maximum dosage: 35 units ½ unit increment
Use replaceable insulin cartridge Use dial mechanism for dose NovoPen® 3 Maximum dosage: 70 units 1 unit increment metal material NovoPen ® Junior Maximum dosage: 35 units ½ unit increment BD™ Pen and Pen Mini 1.5 cc cartridge Maximum dosage: 30 or 15 units

43 Innovo® & InDuo™ InDuo: Integrates two daily activities combined into one device Blood glucose monitoring (OneTouch® Ultra® meter) and Insulin Delivery Device (Innovo) Supports an acceptance and understanding of the link between SMBG and insulin therapy Device serves as a constant reminder to test whenever the patient injects Memory function stores the time elapsed & amount of last insulin dose Uses 3 cc cartridge Maximum dosage: 70 units; 1 unit increments

44 OptiClik FDA approved 8/04
Reusable pen for Lantus & Apidra 1-unit increments; takes only BD pen needles Supplied to physicians; not available in pharmacies

45 Disposable/Prefilled Insulin Pens
Hold 3 cc insulin Discard when finished Use dial mechanism for dose; need to prime (“air shot”) Novolin® InnoLet® Clock-like dial (egg timer-like) with large scale numbers; audible clicks large grip and ergonomic shape that allows alternative grips, easy-to-push large button and support shoulder Maximum dose: 50 units 1 unit increments Regular, NPH and 70/30 insulin only

46 Disposable/Prefilled Insulin Pens, cont.
Novo Nordisk FlexPen ® (Novolog ®, Novolog ® Mix 70/30): up to 60 units; 1 unit increments Eli Lilly pens (Humalog ®,Humalog ® Mix 75/25™, NPH, 70/30): up to 60 units; 1 unit increments

47 Needles 29 G: ½” (12.7mm) 31 G: 3/16” (5 mm) or 5/16” (8 mm) NovoFine®
Pen Needles BD 29 G: ½” (12.7mm) 31 G: 3/16” (5 mm) or 5/16” (8 mm) Novo Nordisk NovoFine® 30 gauge x 1/3” (8mm) 31 gauge x ¼” (6mm) Caution with obese patients if use shorter needles Syringes: 1/3, ½, 1 cc Several times enlarged NovoFine® 30 [30 gauge x 1/3” (8mm)] Disposable Needle


49 Alternate Testing Sites

50 Alternative Site Testing: Cons
Lag time of 5-30 minute between forearm & finger blood flow to finger is 3-5 x faster than arm significant when BG changing rapidly When not to use (use fingers) BG rapidly changing suspect low BG hypoglycemic unawareness within 1-2 hours after meals Bruising at site

51 CGMS  (Continuous Glucose Monitoring System) System Gold™
Other Methods of SMBG Continuous ambulatory blood glucose monitoring CGMS  (Continuous Glucose Monitoring System) System Gold™ Medtronic MiniMed 72-hour; BG recorded q5min 24-hour glucose patterns detect unrecognized hypoglycemia Requires HCP support Noninvasive: GlucoWatch G2 Biographer Cygnus Requires a prescription

52 Self-Monitoring of Blood Glucose (SMBG) - ADA Recommendations
Type 1 Diabetes : 3 x daily Type 2 Diabetes: optimal frequency and timing not known; “sufficient to facilitate reaching glucose goals” Postprandial BG may be necessary to reach A1C goals and/or reduce risk of hypoglycemia Self-management training: how to use the data to adjust food intake, exercise or pharmacologic therapy Diabetes Care 2006

53 Self-Monitoring:Outcomes
Improve overall control: Best studies: HbA1c 0.7% lower in type 1 HbA1c 0.6% lower in type 2 Meta-analysis HbA1c 0.25% lower

54 Other Emerging Therapies
Pharmacologic PPAR/PPAR dual agonists Muraglitazar (Pargluva; Advisory committee met 9/9/05; recommended approval) Tesaglitazar (Galida) Alternative insulin dosage forms (IH, buccal; transdermal; nasal) Inhaled insulin, Exubera Islet cell transplants Rimonabant (Acomplia) Monitoring Continous blood glucose monitoring


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