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Current Advances in Diabetes Management

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1 Current Advances in Diabetes Management
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

2 Change in Age-Adjusted Mortality Rates % Change in Age-Adjusted
50 Diabetes Mortality 40 % Change in Age-Adjusted Mortality Rate Since 1979 30 20 10 Cancer Mortality -10 -20 All-Cause Mortality -30 Major CVD Mortality -40 -50 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year B Sobel et al., Circ 2003; 107:636 (CDC, PMD)

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 Hg Blood pressure <180 mg/dL (<10.0 mmol/L)    Postprandial plasma glucose mg/dL ( mmol/L)    Preprandial plasma glucose <7.0%    A1C Glycemic control Everyone over 40 or with risk factors   Everyone American Diabetes Association. Diabetes Care. 2004;27:s19.

4 63% of Patients With Diabetes are Not At ADA A1C Goal <7%
Adults aged years with previously diagnosed diabetes who participated in the interview and examination components of the National Health Examination Survey (NHANES), 37.2% >8% 63% 7% 7.8% 25.8% 37.0% 17.0% 12.4% A1C % of Subjects n = 404 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 Glycemic Goals of Therapy
Verbal Target ~100 <<200 As low as possible w/o unacceptable AE Goal Premeal plasma glucose (mg/dl) 2-h postprandial plasma glucose HbA1c ADA 90-130 <180* <7%** ACE <110 <140 <6.5% * 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 Diabetes Care 28:s4-36, 2005

7 Effect of Early TZD Use on A1C
6.8 - 6.6 - 6.4 - 6.2 - 6.0 - 5.8 - 5.6 - 5.4 - 5.2 - 5.0 - Rosiglitazone (n=39) Pioglitazone (n=62) Control (n=71) * A1C (%) * * * * * * * P<0.001 vs. baseline; † P<0.001 vs. rosiglitazone and pioglitazone Baseline Switch 2-yr check 3-yr final Durbin RJ Diabetes, Obesity & Metabolism 6: , 2004

8 Patients Remain on Monotherapy >1 Year After First A1c >8.0%*
Length of time that the patient’s A1c remained above 8.0% before a switch/addition in therapy* 25 20 months 20 14 months Months 15 10 5 Metformin Only Sulfonylurea Only (n=354) (n=2517) * 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.

9 Effectiveness of Medical Nutrition Therapy in Management of Type 2 Diabetes
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. No nutrition education 1 visit with dietitian 3 visits with dietitian 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 Initial 6 week 3 month 6 month * A1C (%) *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 Franz MJ et al. J Am Diet Assoc. 1995;95:

10 Progressive Hyperglycemia Despite Insulin, Sulfonylurea, or Metformin
9 Conventional Glibenclamide Metformin 8 Chlorpropamide Insulin Median HbA1c (%) 7 6 2 4 6 8 10 Years from randomization UKPDS 34, Lancet 1998.

11 As Patients Get Closer to A1c Goal, the Need to Manage PPG Increases
20 40 60 80 100 30% 50% 55% 60% 70% % Contribution FPG PPG 70% 50% 45% 40% As Patients Get Closer to A1C Goal, the Need to Successfully Manage PPG Significantly Increases Postprandial glycemic excursions become more predominant in patients with good control of fasting plasma glucose. Therefore, treatment should focus on both FPG and PPG excursions in order to reach and maintain A1C targets. Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26: 30% >10.2 <7.3 A1C Range (%) Monnier L, et al. Diabetes Care. 2003;26:

12 Anti-Hyperglycemic Agents in Type 2 Diabetes

13 Glycemic Control

14 Treatment Algorithm - Glucose
Diagnosis by screening or with symptoms Lifestyle Intervention nutrition, exercise, education 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 Yes Quarterly to semi-annual follow-up Are A1c/FPG Targets Achieved? Target Insulin Resistance No Target PPG Target Insulin Deficiency FPG > 200 mg/dL FPG < 130 mg/dL

15 Diabetes-related Deaths: UKPDS Overweight Subgroup
Proportion of Patients With Events 0% 10% 20% 30% 40% 3 6 9 12 15 Years from randomization Conventional (n=411) Insulin or SFU (n=951) Metformin (n=342) M v C P=.017 M v I P=0.11 Lancet. 1998;352:837.

16 Insulin Resistance: Cardiovascular Correlates
X TZD Glitazone Effects Accelerated Atherosclerosis Improves glycemic control Reduces blood pressure Type 2 diabetes Hypertension Modulates adipocytokines and inflammatory markers Decreases TG (P) Increases HDL Improves LDL size Insulin Inflammation Dyslipidemia Resistance In addition to type 2 diabetes, insulin resistance is a pathogenic factor in the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricemia, polycystic ovary disease, and obesity. Reverses of coagulation and fibrinolytic defects Reduces central obesity Coagulation/Fibrinolytic defects Obesity (central) Improves endothelial dysfunction Endothelial dysfunction Adapted from Diabetes Care 21: , 1998.

17 Ongoing Clinical Trials
Charbonnel B, et al. Diabetes Care 27:1647–1653, 2004 RECORD (Rosiglitazone Evaluated for CVD Outcomes & Regulation of Glucose in Diabetes) 6,000 patients (add Rosi to exisiting Rx) – 6 year follow-up 1° Endpoint = combined cardiovascular events BARI 2D (Bypass Angioplasy Revascularization Inverstigation – Type 2 Diabetes) Medical management vs. revascularization – of early CAD Comparison of insulin sensitizing vs. insulin providing therapies

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

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

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 Δ A1C (%) Δ Body Weight (kg) Placebo Controlled Placebo Controlled Open-Label Extensions Open-Label Extensions 0.0 -2 -0.5 5.5±0.5 kg 1.2±0.1% -1.0 -4 -1.5 -6 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 Duration of Treatment (Years) Duration of Treatment (Years) Baseline A1C 8.2% Baseline weight: 100 kg

23 General Prescribing Considerations: Dosing
Initiation 1 Mo 5 mcg BID Stable Dose 10 mcg BID Required DISCUSSION POINTS: Flowchart shows typical treatment initiation and dose escalation schedule. When BYETTA treatment initiation is being considered, the prescriber should evaluate any current dose of sulfonylurea and decide if the dose should be reduced to help reduce the risk of hypoglycemia when BYETTA is added to the current treatment regimen. BYETTA treatment is initiated with the pre-filled pen that delivers fixed 5 mcg doses, and BYETTA should be administered SC BID within 60 minutes before the morning and evening meals. After the first month of treatment with 5 mcg doses of BYETTA, prescriber should assess how well the patient has tolerated BYETTA treatment. If the patient has tolerated BYETTA treatment well, the BYETTA dose can be increased by prescribing the pre-filled pen that delivers fixed 10 mcg doses, and BYETTA should continue to be administered SC BID within 60 minutes before the morning and evening meals. If, after the first month of treatment with 5 mcg doses of BYETTA, prescriber determines patient is not yet able to effectively manage any nausea associated with BYETTA, the 5 mcg dosing BID can be continued until the prescriber and patient determine that BYETTA is being tolerated well enough that the dose can be increased to 10 mcg SC BID. 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, 2005. Pramlintide Clinical Use A

24 General Prescribing Considerations: Administration and Storage
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 Required DISCUSSION POINTS: No slide notes necessary – speakers’ oral presentation should just mimic the slide text. Exenatide Prescribing Information, 2005.

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

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

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

28 Insulin Pens Novo Lilly Others

29 Intensive Management Strategy
Monomeric Insulin Analog Insulin Effect Glargine Met + Glitazone (+ Secretagogue) Brfst Lunch Dinner Bed 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)

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 Amylin is an important regulator of glucose influx into the bloodstream. It was first isolated and characterized at Oxford University from amyloid deposits in the islets of Langerhans. A 37-amino acid peptide, amylin is colocated and cosecreted with insulin from the pancreatic -cells. The photomicrographs on this slide show amylin and insulin expression in pancreatic islet cells. Amylin is not synonymous with amyloid deposits, which are often seen in the islets of patients with type 2 diabetes and are thought to be the result of overproduction and aggregation of amylin in patients with insulin resistance. The contribution, if any, of islet amyloid deposits to the pathology of type 2 diabetes is unknown. Unger. Williams Textbook of Endocrinology Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology. 8th ed. Philadelphia, Pa: W.B. Saunders Company; 1992:

31 Amylin Is Deficient in Diabetes
Sustacal® 5 10 15 20 No diabetes Plasma Amylin (pM) Insulin-treated type 2 diabetes Type 1 diabetes As with insulin, production of amylin declines with -cell deterioration. In type 1 diabetes, total destruction of the -cells results in the virtual absence of amylin. In type 2 diabetes, there is still postprandial secretion of amylin, but it is greatly reduced. Fineman MS, Giotta MP, Thompson RG, et al. Amylin response following Sustacal® ingestion is diminished in type II diabetic patients treated with insulin. Diabetologia. 1996;39(suppl 1):A149. Kruger DF, Gatcomb PM, Owen SK. Clinical implications of amylin and amylin deficiency. Diabetes Educ. 1999;25: -30 30 60 90 120 150 180 Minutes After Sustacal® Fineman. Diabetologia. 1996;39(suppl 1):A149. Kruger. Diabetes Educ. 1999;25:389.

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

33 Pramlintide Clinical Effects TYPE 2 DIABETES COMBINED PIVOTALS
Placebo + Insulin 120 g Pramlintide BID + Insulin  A1C (%)  Insulin Use (%)  Weight (kg) Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 8 1 Modified Slide Index PE0014 L: A,B DISCUSSION POINTS: Post hoc analysis of pooled data from patients with type 2 diabetes who received 120 g BID pramlintide doses in pivotal Phase 3 studies. pramlintide treated subjects had an overall reduction in A1C, with less insulin used, and reductions in weight compared with placebo. SLIDE BACKGROUND: Pivotal Studies (122 and 123) were double-blind, placebo-controlled, fixed pramlintide dose, fixed insulin dose, and patients tended to reside in more generalist practices Reference: Amylin_Adhoc_12_SDS_1_Adhoc_13_ADA_1,2,4. pramlintide_PI_and_Med_Guide2005_p7.pdf 6 -0.2 4 -0.4 2 ** -1 ** -0.6 ** -2 * ** ** ** ** -0.8 -4 -2 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) Dose Units 15 µg 2.5 U 30 µg 5 U DISCUSSION POINTS: pramlintide should be administered subcutaneously immediately prior to each major meal (250 kcal or containing 30 g of carbohydrate). pramlintide and insulin should not be mixed and must be administered separately, because the pharmacokinetic parameters of pramlintide were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. pramlintide doses are expressed in micrograms. Doses are measured and delivered using insulin syringes; conversion table provided on this slide. Storage guidelines are similar to those for insulin. SLIDE BACKGROUND: pramlintide_PI_and_Med_Guide2005_p18.pdf 45 µg 7.5 U 60 µg 10 U 120 µg 20 U Pramlintide Prescribing Information, 2005

35 Lipids

36 Statins: Effective Agents to Reduce CVD
PROVE-IT CARE 4S LIPID HPS TNT 25 20 % With CAD Event 15 10 WOSCOPS AFCAPS HPS (estimated) Results of HPS, together with the results from the WOSCOPS and AFCAPS/ TexCAPS trials, show that the benefits of LDL-C lowering with statin therapy in primary prevention of CAD are seen across the broad range of baseline plasma LDL-C concentrations. Together with the results from the 4S, CARE, and LIPID trials, HPS has also established the benefits of LDL-C reduction with statin therapy in secondary prevention of CAD in patients with a wide range of baseline plasma LDL-C concentrations. 5 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL) Adapted from Illingworth. Med Clin North Am. 2000;84:23. Available at: Illingworth DR. Management of hypercholesterolemia. Med Clin North Am. 2000;84: At:

37 VA-HIT: Effects of Gemfibrozil on CVD Events in CHD Patients With Low HDL-C
10 6.0* -30 -25 -20 -15 -10 -5 5 % Change From Baseline 4 -31* LDL-C HDL-C TG All-Cause Mortality -22‡ -11 -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 *P<0.001; †P=0.006; ‡P=0.07. Rubins HB, et al. N Engl J Med. 1999;341:

38 Comprehensive Management of Dyslipidemia
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

39 Blood Pressure

40 HOT Trial 48% Effect of Diastolic Target on CVD Events - 4 Years 24.4
30 48% Risk Reduction 24.4 20 Events/ 1000 Pt-Yrs 18.6 10 11.9 9.9 10.0 9.3 <90 <85 <80 <90 <85 <80 Diabetic Patients n=1,501, P=0.016 Non-Diabetic Patients n=18,790, P=NS Lancet 351: , 1998

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 Treatment Algorithm—Hypertension
BP > 130/80 mm Hg 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? Thiazide Monthly to quarterly follow-up No -blocker Coronary Disease Albuminuria/CVD Risk Factors ACE/ARB 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

43 Multifactorial Intervention for Type 2 DM: Steno-2 Study
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:

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

45 Multifactorial Intervention for Type 2 DM: Steno-2 Study (cont)
60 Intensive Therapy P=0.007 Hazard Ratio=0.47 (95% CI, ; P=0.008) 53% Conventional Therapy 50 40 Primary Composite End Point (%) 30 The time-to-first-event curves for the primary composite endpoint diverged throughout 7.8 years of follow-up in the Steno-2 study. The study compared the effects of conventional therapy with intensive therapy on CVD in patients with type 2 diabetes and microalbuminuria. Patients receiving intensive therapy had a significantly lower risk of developing CVD than those in the conventional-treatment group (unadjusted HR, 0.47; 95% CI, ). Adjustment for the duration of diabetes, age, sex, smoking status, and presence or absence of CVD at baseline had no substantial effect. 20 10 12 24 36 48 60 72 84 96 Months of Follow-up Gaede P, et al. N Engl J Med. 2003;348: Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:


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