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John B. Buse, MD, PhD Associate Professor of Medicine Chief, Division of General Medicine and Clinical Epidemiology Director, Diabetes Care Center University.

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Presentation on theme: "John B. Buse, MD, PhD Associate Professor of Medicine Chief, Division of General Medicine and Clinical Epidemiology Director, Diabetes Care Center University."— Presentation transcript:

1 John B. Buse, MD, PhD Associate Professor of Medicine Chief, Division of General Medicine and Clinical Epidemiology Director, Diabetes Care Center University of North Carolina Chapel Hill, NC Current Advances in Diabetes Management

2 Change in Age-Adjusted Mortality Rates B Sobel et al., Circ 2003; 107:636 (CDC, PMD) Diabetes Mortality Cancer Mortality All-Cause Mortality Major CVD Mortality Year % Change in Age- Adjusted Mortality Rate Since 1979

3 ABC’s of Diabetes Management Smoking cessation Antiplatelet therapy >40 mg/dL (>1.1 mmol/L) HDL-cholesterol <150 mg/dL (<1.7 mmol/L) Triglycerides <100 mg/dL (<2.6 mmol/L) LDL-cholesterol Lipids <130/80 mm HgBlood pressure <180 mg/dL (<10.0 mmol/L) Postprandial plasma glucose mg/dL ( mmol/L) Preprandial plasma glucose <7.0% A1C Glycemic control American Diabetes Association. Diabetes Care. 2004;27:s19. Everyone over 40 or with risk factors Everyone

4 63% of Patients With Diabetes are Not At ADA A1C Goal <7% 37.2% >8% 63%  7% 7.8% 25.8% 37.0% 17.0% 12.4% % of Subjects n = 404 A1C Adults aged years with previously diagnosed diabetes who participated in the interview and examination components of the National Health Examination Survey (NHANES), Only 7% of adults with diabetes in NHANES attained: A1C level <7% Blood pressure <130/80 mm Hg Total cholesterol <200 mg/dL Saydah SH et al. JAMA. 2004;291:

5 Difficulties in Achieving Target A1C Values What is the appropriate A1C target Challenges – Late diagnosis and initiation of therapy – Therapeutic inertia – Lack of effective lifestyle intervention – Secondary failure – Adverse events associated with antihyperglycemic therapies – Complexity of care – Role of postprandial glucose in failure

6 Diabetes Care 28:s4-36, Goal Premeal plasma glucose (mg/dl) 2-h postprandial plasma glucose HbA1c ADA <180* <7%** ACE <110 <140 <6.5% Glycemic Goals of Therapy * Evaluation and treatment of postprandial glucose may be useful in the setting of suspected postprandial hyperglycemia, with the use of agents targeting postprandial hyperglycemia and for suspected hypoglycemia. ** More stringent glycemic goals (i.e. a normal A1C, <6%) may further reduce complications at the cost of increased risk of hypoglycemia Verbal Target ~100 <<200 As low as possible w/o unacceptable AE

7 Effect of Early TZD Use on A1C A1C (%) Baseline Switch 2-yr check 3-yr final * * * * * * * † † Rosiglitazone (n=39) Pioglitazone (n=62) Control (n=71) Durbin RJ Diabetes, Obesity & Metabolism 6: , 2004 * P<0.001 vs. baseline; † P<0.001 vs. rosiglitazone and pioglitazone

8 Patients Remain on Monotherapy >1 Year After First A1c >8.0% * *May include up-titration. Length of time between first A1c >8.0% and switch/addition in therapy could include periods where patients had subsequent A1c test values below 8%. Based on nonrandomized retrospective database analysis. Data from Kaiser Permanente Northwest Patients had to be continuously enrolled for 12 months with A1c lab values. Brown et al. Diabetes. 2003;52(suppl 1):A61-A62. Abstract 264-OR. Length of time that the patient’s A1c remained above 8.0% before a switch/addition in therapy* Metformin OnlySulfonylurea Only Months (n=354) (n=2517) 14 months 20 months

9 Franz MJ et al. J Am Diet Assoc. 1995;95: * P<0.05 for 3-visit and 1-visit groups vs no nutrition education † No significant difference between 3-visit and 1-visit groups: P<0.001 significantly less than at entry No nutrition education 1 visit with dietitian 3 visits with dietitian A1C (%) Effectiveness of Medical Nutrition Therapy in Management of Type 2 Diabetes Initial6 week3 month6 month * † † Emphasize blood glucose control, not weight loss. Focus on carbohydrate foods, portions, and number of servings per meal. Encourage physical activity. Use food records with blood glucose monitoring data.

10 Progressive Hyperglycemia Despite Insulin, Sulfonylurea, or Metformin Years from randomization Chlorpropamide Conventional Glibenclamide Insulin Metformin Median HbA 1c (%) UKPDS 34, Lancet 1998.

11 As Patients Get Closer to A1c Goal, the Need to Manage PPG Increases Monnier L, et al. Diabetes Care. 2003;26: % 40% 45% 50% 70% 60% 55% 50% 30% > <7.3 FPG PPG % Contribution A1C Range (%)

12 Anti-Hyperglycemic Agents in Type 2 Diabetes

13 Glycemic Control

14 Diagnosis by screening or with symptoms Target Insulin Resistance No Treatment Algorithm - Glucose Yes Quarterly to semi-annual follow-up Lifestyle Intervention nutrition, exercise, education Are A1c/FPG Targets Achieved? Target PPG Target Insulin Deficiency FPG > 200 mg/dL FPG < 130 mg/dL Monthly to quarterly follow-up * *Keep adding agents until target is reached. Self-titration at home when possible. Metformin, glitazone Exenatide, nateglinide, α-glucosidase inhibitors, rapid-acting insulin, pramlintide SFUs/glinide, insulin, exenatide

15 M v I P=0.11 M v C P=.017 Lancet. 1998;352: Proportion of Patients With Events 0% 10% 20% 30% 40% Years from randomization Conventional (n=411) Insulin or SFU (n=951) Metformin (n=342) Diabetes-related Deaths: UKPDS Overweight Subgroup

16 Insulin Resistance: Cardiovascular Correlates Type 2 diabetes Hypertension Obesity (central) Dyslipidemia Endothelial dysfunction Coagulation/Fibrinolytic defects Insulin Resistance Adapted from Diabetes Care 21: , Accelerated Atherosclerosis Inflammation X TZD Glitazone Effects Reduces blood pressure Reduces central obesity Improves endothelial dysfunction Reverses of coagulation and fibrinolytic defects Decreases TG (P) Increases HDL Improves LDL size Improves glycemic control Modulates adipocytokines and inflammatory markers

17 Charbonnel B, et al. Diabetes Care 27:1647–1653, 2004 RECORD ( R osiglitazone E valuated for C VD O utcomes & R egulation of Glucose in D iabetes) 6,000 patients (add Rosi to exisiting Rx) – 6 year follow-up 1° Endpoint = combined cardiovascular events BARI 2D ( B ypass A ngioplasy R evascularization I nverstigation – Type 2 D iabetes) Medical management vs. revascularization – of early CAD Comparison of insulin sensitizing vs. insulin providing therapies Ongoing Clinical Trials

18 Pioglitazone Comparator Studies – Europe Durability R. Urquhart. IDF 2003.

19 Glitazones: Minimizing Adverse Effects Warn patients about the possible (liver) and expected adverse effects (edema and weight gain); develop prospectively a plan for home evaluation & management ALT measurements prior to initiating therapy and intermittently thereafter; avoid use in active liver disease. Start with a low dose in high risk patients (pre-existing edema, insulin treated or known heart disease) – Pioglitazone 15 mg po qd or rosiglitazone 2-4 mg po qd – At 1-2 month follow-up visit, increase dose as needed – If edema develops, salt restriction ± low-dose thiazide diuretic ± loop diuretic ± dose reduction – Consider role of ACE inhibition, CCB’s, NSAID’s Buse JB. Circulation. 108(8):e57, Nesto RW. Circulation. 108(23):2941-8, 2003.

20 Insulin sensitization – Diet/exercise + glitazone + metformin (if FPG > 110 mg/dl) – Minimal risk of hypoglycemia – Minimize weight gain Met + Glitazone BrfstLunchSupperBed Insulin Effect Intensive Management Strategy: Step 1

21 Multiple Sites of Action of Exenatide CNS: Promotes satiety and reduction of appetite Stomach: Slows gastric emptying Beta cell: Stimulates glucose- dependent insulin secretion Increases beta cell mass Alpha cell: Inhibits glucagon secretion in a glucose dependent fashion Liver: Reduces hepatic glucose output by inhibiting glucagon release

22 A1C and Body Weight Reductions: Preliminary Analysis for Subjects Treated for 2 Years 2 yr data for 82-wk cohort (N = 146) Mean ± SE Duration of Treatment (Years) Placebo Controlled Open-Label Extensions Baseline A1C 8.2% Δ A1C (%) Placebo Controlled Open-Label Extensions Baseline weight: 100 kg Duration of Treatment (Years) Δ Body Weight (kg) 1.2±0.1% 5.5±0.5 kg

23 Initiation  1 Mo 5 mcg BID Stable Dose 10 mcg BID Stable Dose Evaluate need for SFU dose reduction to minimize risk of hypoglycemia No dosage adjustments based on meal size or exercise No additional glucose monitoring required Exenatide Prescribing Information, General Prescribing Considerations: Dosing

24 SC injection – Administer BID within 60 minutes before morning and evening meals (do not give after meal) – Abdomen, thighs, and arms Missed dose – Wait until the next scheduled dose Refrigeration – Refrigerate (36°-46° F) between injections – Do not freeze – Discard 30 days after first use General Prescribing Considerations: Administration and Storage Exenatide Prescribing Information, 2005.

25 Insulin sensitizers + secretagogue – Glitazone +/- metformin – + exenatide (or sulfonylurea or “glinide”) Metformin + Glitazone + Secretagogue BrfstLunchSupperBed Insulin Effect Intensive Management Strategy: Step 2

26 Glargine vs. Exenatide ITT patient sample Mean ± SE shown * p<0.0001, exenatide vs insulin glargine at same time point  Body Weight (lbs) * * * * * *  HbA1c (%) Heine RJ, et al. ADA Scientific Sessions, June 2005

27 OAH’s Ready for injected therapy Coverage: FPG PPG x 1-2 Coverage: Only FPG Coverage: FPG PPG x 2 Coverage: FPG PPG x 3 Premix QD Premix BID Analog premix TID Coverage: FPG PPG x 1 Coverage: FPG PPG x 3 MDI lite 2-3 shots MDI 4 shots 1 shot basal Options to Individualize Therapy in Patients Failing Oral Anti-Hyperglycemic Therapy ??? Exenatide BID Coverage: FPG PPG x 3

28 Insulin Pens Novo Lilly Others

29 Insulin sensitizer(s) + secretagogue (SFU or “glinide”) Add glargine or NPH QHS; titrate to normalize fasting glucose Add monomeric insulin analog QAC; titrate to normalize postprandial glucose (generally discontinue secretagogue) Met + Glitazone (+ Secretagogue) BrfstLunchDinnerBed Insulin Effect Glargine Monomeric Insulin Analog Intensive Management Strategy

30 Amylin: The Second  -Cell Hormone First reported in 1987 Important regulator of glucose influx into bloodstream 37–amino acid neuroendocrine hormone Co-located and co-secreted with insulin from pancreatic  -cells Not synonymous with “amyloid deposits” Amylin Insulin Unger. Williams Textbook of Endocrinology

31 Amylin Is Deficient in Diabetes Minutes After Sustacal ® No diabetes Type 1 diabetes Plasma Amylin (pM) Fineman. Diabetologia. 1996;39(suppl 1):A149. Kruger. Diabetes Educ. 1999;25:389. Insulin-treated type 2 diabetes Sustacal ®

32 Multiple Sites of Action of Pramlintide CNS: Promotes satiety and reduction of appetite Stomach: Slows gastric emptying Beta cell: None Alpha cell: Inhibits glucagon secretion Liver: Reduces hepatic glucose output by inhibiting glucagon release

33 Pramlintide Clinical Effects TYPE 2 DIABETES COMBINED PIVOTALS * **  Insulin Use (%)  A1C (%)  Weight (kg) Week 4Week 13Week 26Week 4Week 13Week 26 Week 4Week 13Week 26 Placebo + Insulin 120  g Pramlintide BID + Insulin Placebo + insulin (n=284), Baseline A1C = 9.3% Pramlintide + insulin (n=292), Baseline A1C = 9.1% *P <0.01, **P <0.0001; ITT population; Mean (SE) change from baseline Pramlintide Prescribing Information, Data on file, Amylin Pharmaceuticals, Inc. Hollander P, et al. Diabetes Care 2003; 26: Ratner RE, et al. Diabetes Technol Ther 2002; 4:51-61

34 Pramlintide + Insulin: General Considerations Administration SC injection into abdomen or thigh Do not mix with insulin Pramlintide and insulin should always be given as separate injections and at separate sites at least 2 inches apart Administer using U-100 insulin syringe Inject before each major meal (and snack  250 kcal or  30 g CHO) Pramlintide Prescribing Information, U120 µg 10 U60 µg 7.5 U45 µg 5 U30 µg 2.5 U15 µg UnitsDose

35 Lipids

36 Statins: Effective Agents to Reduce CVD Adapted from Illingworth. Med Clin North Am. 2000;84:23. Available at: % With CAD Event WOSCOPS AFCAPS HPS (estimated) LDL-C (mg/dL) PROVE-IT CARE 4S LIPID HPS TNT

37 VA-HIT: Effects of Gemfibrozil on CVD Events in CHD Patients With Low HDL-C *P<0.001; † P=0.006; ‡ P=0.07. Rubins HB, et al. N Engl J Med. 1999;341: * % Change From Baseline 4 -31* LDL-C HDL-C TG All-Cause Mortality -22 ‡ † Nonfatal MI/CHD Death CHD Death Stroke Subjects: 2531 men Age: ≤74 (avg 64) yr Mean baseline LDL-C: 111 mg/dL Mean baseline HDL-C: 32 mg/dL Mean baseline TG: 161 mg/dL Duration of Type 2 DM: 7 yr Intervention: Gemfibrozil 600 mg BID

38 Increased Triglycerides VLDL Small dense LDL LDL Apo B Decreased HDL Apo A-I DM Rx Fibrates Niacin Fish oil Statins Bile acid sequestrants Chol. absorption inhibitors Stanol esters Comprehensive Management of Dyslipidemia

39 Blood Pressure

40 Effect of Diastolic Target on CVD Events - 4 Years HOT Trial Lancet 351: , <90<85<80<90<85< % Risk Reduction Events/ 1000 Pt-Yrs Diabetic Patients n=1,501, P=0.016 Non-Diabetic Patients n=18,790, P=NS

41 Number of Medications to Achieve Goal BP in 5 Trials of DM &/or Renal Disease Bakris. J Clin Hypertens 1999;1:141-7

42 BP > 130/80 mm Hg Treatment Algorithm—Hypertension Lifestyle Intervention Diet (FFV, low-fat dairy, low Na, modest E to H) Weight loss Exercise (30 minutes most days of the week) Smoking cessation Yes Quarterly to semi-annual follow-up SBP <130 and DBP <80? Virtually all two-drug combinations should include a thiazide diuretic The third drug could (should) be a calcium channel blocker In the setting of kidney or heart disease, consider adding a furosemide BID or torsemide In the setting of kidney disease and significant proteinuria, consider combined ACE/ARB therapy Thiazide Monthly to quarterly follow-up No  -blocker Coronary Disease Albuminuria/CVD Risk Factors ACE/ARB

43 160 Patients With Type 2 Diabetes and Albuminuria Mean baseline characteristics Age: 55 yr BMI: 30 Duration of DM: ~5.8 yr A1c: 8.6% Randomized to conventional or intensive therapy Mean follow-up: 7.8 yr Gaede P, et al. Lancet. 1999;353: Gaede P, et al. N Eng J Med. 2003;348: Multifactorial Intervention for Type 2 DM: Steno-2 Study

44 Gaede P, et al. Lancet. 1999;353: Gaede P, et al. N Eng J Med. 2003;348: Physiologic Measures at End of Study ConventionalIntensive A1c, % ~9.0~7.8 Systolic BP mm Hg ~148~132 LDL chol mg/dL ~130~75 TG mg/dL ~260~150 Multifactorial Intervention for Type 2 DM: Steno-2 Study (cont)

45 Primary Composite End Point (%) Conventional Therapy Months of Follow-up Gaede P, et al. N Engl J Med. 2003;348: Intensive Therapy P=0.007 Hazard Ratio=0.47 (95% CI, ; P=0.008) 53% Multifactorial Intervention for Type 2 DM: Steno-2 Study (cont)

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