Presentation on theme: "Current Advances in Diabetes Management"— Presentation transcript:
1 Current Advances in Diabetes Management John B. Buse, MD, PhDAssociate Professor of MedicineChief, Division of General Medicine and Clinical EpidemiologyDirector, Diabetes Care CenterUniversity of North CarolinaChapel Hill, NC
2 Change in Age-Adjusted Mortality Rates % Change in Age-Adjusted 50Diabetes Mortality40% Change in Age-AdjustedMortality Rate Since 1979302010Cancer Mortality-10-20All-Cause Mortality-30Major CVD Mortality-40-501980198119821983198419851986198719881989199019911992199319941995199619971998YearB Sobel et al., Circ 2003; 107:636 (CDC, PMD)
3 ABC’s of Diabetes Management Smoking cessationAntiplatelet 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-cholesterolLipids<130/80 mm HgBlood pressure<180 mg/dL (<10.0 mmol/L) Postprandial plasma glucosemg/dL ( mmol/L) Preprandial plasma glucose<7.0% A1CGlycemic controlEveryone over 40 or with risk factors EveryoneAmerican 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 Subjectsn = 404Only 7% of adults with diabetes in NHANES attained:A1C level <7%Blood pressure <130/80 mm HgTotal cholesterol <200 mg/dLSaydah SH et al. JAMA. 2004;291:
5 Difficulties in Achieving Target A1C Values What is the appropriate A1C targetChallengesLate diagnosis and initiation of therapyTherapeutic inertiaLack of effective lifestyle interventionSecondary failureAdverse events associated with antihyperglycemic therapiesComplexity of careRole of postprandial glucose in failure
6 Glycemic Goals of Therapy Verbal Target~100<<200As low aspossible w/o unacceptable AEGoalPremeal plasma glucose (mg/dl)2-h postprandial plasma glucoseHbA1cADA90-130<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 hypoglycemiaDiabetes 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 pioglitazoneBaselineSwitch2-yr check3-yr finalDurbin 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*2520 months2014 monthsMonths15105Metformin OnlySulfonylurea 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 education1 visit with dietitian3 visits with dietitian6.66.87.07.220.127.116.11.08.28.4Initial6 week3 month6 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 entryFranz MJ et al. J Am Diet Assoc. 1995;95:
10 Progressive Hyperglycemia Despite Insulin, Sulfonylurea, or Metformin 9ConventionalGlibenclamideMetformin8ChlorpropamideInsulinMedian HbA1c (%)76246810Years from randomizationUKPDS 34, Lancet 1998.
11 As Patients Get Closer to A1c Goal, the Need to Manage PPG Increases 2040608010030%50%55%60%70%% ContributionFPGPPG70%50%45%40%As Patients Get Closer to A1C Goal, the Need to Successfully Manage PPG Significantly IncreasesPostprandial 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<7.3A1C Range (%)Monnier L, et al. Diabetes Care. 2003;26:
14 Treatment Algorithm - Glucose Diagnosisby screening or with symptomsLifestyle Interventionnutrition, exercise, educationMonthly to quarterly follow-up**Keep adding agents until target is reached. Self-titration at home when possible.Metformin, glitazoneExenatide, nateglinide, α-glucosidase inhibitors, rapid-acting insulin, pramlintideSFUs/glinide, insulin, exenatideYesQuarterly to semi-annual follow-upAre A1c/FPG Targets Achieved?Target Insulin ResistanceNoTarget PPGTarget Insulin DeficiencyFPG > 200 mg/dLFPG < 130 mg/dL
15 Diabetes-related Deaths: UKPDS Overweight Subgroup Proportion of Patients With Events0%10%20%30%40%3691215Years from randomizationConventional (n=411)Insulin or SFU (n=951)Metformin (n=342)M v C P=.017M v I P=0.11Lancet. 1998;352:837.
16 Insulin Resistance: Cardiovascular Correlates XTZDGlitazone EffectsAccelerated AtherosclerosisImproves glycemic controlReduces blood pressureType 2 diabetesHypertensionModulates adipocytokines and inflammatory markersDecreases TG (P)Increases HDLImproves LDL sizeInsulinInflammationDyslipidemiaResistanceIn 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 defectsReduces central obesityCoagulation/Fibrinolytic defectsObesity (central)Improves endothelial dysfunctionEndothelial dysfunctionAdapted from Diabetes Care 21: , 1998.
17 Ongoing Clinical Trials Charbonnel B, et al. Diabetes Care 27:1647–1653, 2004RECORD (Rosiglitazone Evaluated for CVD Outcomes & Regulation of Glucose in Diabetes)6,000 patients (add Rosi to exisiting Rx) – 6 year follow-up1° Endpoint = combined cardiovascular eventsBARI 2D (Bypass Angioplasy Revascularization Inverstigation – Type 2 Diabetes)Medical management vs. revascularization – of early CADComparison 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 & managementALT 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 qdAt 1-2 month follow-up visit, increase dose as neededIf edema develops, salt restriction ± low-dose thiazide diuretic ± loop diuretic ± dose reductionConsider role of ACE inhibition, CCB’s, NSAID’sBuse JB. Circulation. 108(8):e57, Nesto RW. Circulation. 108(23):2941-8, 2003.
21 Multiple Sites of Action of Exenatide CNS:Promotes satiety and reduction of appetiteLiver: Reduces hepatic glucose output by inhibiting glucagon releaseBeta cell:Stimulates glucose-dependent insulin secretionIncreases beta cell massAlpha cell: Inhibits glucagon secretion in a glucose dependent fashionStomach: 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 ± SEΔ A1C (%)Δ Body Weight (kg)PlaceboControlledPlaceboControlledOpen-Label ExtensionsOpen-Label Extensions0.0-2-0.55.5±0.5 kg1.2±0.1%-1.0-4-1.5-60.00.51.01.52.00.00.51.01.52.0Duration of Treatment (Years)Duration of Treatment (Years)Baseline A1C 8.2%Baseline weight: 100 kg
23 General Prescribing Considerations: Dosing Initiation1 Mo5 mcg BIDStable Dose10 mcg BIDRequiredDISCUSSION 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 hypoglycemiaNo dosage adjustments based on meal size or exerciseNo additional glucose monitoring requiredExenatide Prescribing Information, 2005.Pramlintide Clinical UseA
24 General Prescribing Considerations: Administration and Storage SC injectionAdminister BID within 60 minutes before morning and evening meals (do not give after meal)Abdomen, thighs, and armsMissed doseWait until the next scheduled doseRefrigerationRefrigerate (36°-46° F) between injectionsDo not freezeDiscard 30 days after first useRequiredDISCUSSION POINTS:No slide notes necessary – speakers’ oral presentation should just mimic the slide text.Exenatide Prescribing Information, 2005.
26 Glargine vs. Exenatide * * * * * * HbA1c (%) Body Weight (lbs) ITT patient sampleMean ± SE shown* p<0.0001, exenatide vs insulin glargine at same time pointHeine RJ, et al. ADA Scientific Sessions, June 2005
27 Ready for injected therapy Options to Individualize Therapy in Patients Failing Oral Anti-Hyperglycemic Therapy1 shot basalMDI lite 2-3 shotsMDI 4 shotsReady for injected therapyCoverage:Only FPGCoverage: FPG PPG x 1-2Coverage: FPG PPG x 3OAH’sPremix QDPremixBIDAnalog premixTIDCoverage: FPG PPG x 1Coverage: FPG PPG x 2Coverage: FPG PPG x 3Analog Premixes: More Options to Individualize and Fewer Injections???ExenatideBIDCoverage: FPG PPG x 3
29 Intensive Management Strategy Monomeric Insulin AnalogInsulin EffectGlargineMet + Glitazone (+ Secretagogue)BrfstLunchDinnerBedInsulin sensitizer(s) + secretagogue (SFU or “glinide”)Add glargine or NPH QHS; titrate to normalize fasting glucoseAdd monomeric insulin analog QAC; titrate to normalize postprandial glucose (generally discontinue secretagogue)
30 Amylin: The Second -Cell Hormone First reported in 1987Important regulator of glucose influx into bloodstream37–amino acid neuroendocrine hormoneCo-located and co-secreted with insulin from pancreatic -cellsNot synonymous with “amyloid deposits”AmylinInsulinAmylin 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 EndocrinologyUnger 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®5101520No diabetesPlasma Amylin(pM)Insulin-treated type 2 diabetesType 1 diabetesAs 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:-30306090120150180Minutes 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 appetiteLiver: Reduces hepatic glucose output by inhibiting glucagon releaseBeta cell:NoneAlpha cell: Inhibits glucagon secretionStomach: Slows gastric emptying
33 Pramlintide Clinical Effects TYPE 2 DIABETES COMBINED PIVOTALS Placebo + Insulin120 g Pramlintide BID + Insulin A1C (%) Insulin Use (%) Weight (kg)Week 4Week 13Week 26Week 4Week 13Week 26Week 4Week 13Week 2681Modified Slide Index PE0014L: A,BDISCUSSION 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 practicesReference: Amylin_Adhoc_12_SDS_1_Adhoc_13_ADA_1,2,4.pramlintide_PI_and_Med_Guide2005_p7.pdf6-0.24-0.42**-1**-0.6**-2*********-0.8-4-2Placebo + 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 baselinePramlintide 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 AdministrationSC injection into abdomen or thighDo not mix with insulinPramlintide and insulin should always be given as separate injections and at separate sites at least 2 inches apartAdminister using U-100 insulin syringeInject before each major meal (and snack 250 kcal or 30 g CHO)DoseUnits15 µg2.5 U30 µg5 UDISCUSSION 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.pdf45 µg7.5 U60 µg10 U120 µg20 UPramlintide Prescribing Information, 2005
36 Statins: Effective Agents to Reduce CVD PROVE-ITCARE4SLIPIDHPSTNT2520% With CAD Event1510WOSCOPSAFCAPSHPS (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.5507090110130150170190210LDL-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 106.0*-30-25-20-15-10-55% Change From Baseline4-31*LDL-CHDL-CTGAll-Cause Mortality-22‡-11-22†Nonfatal MI/CHD DeathCHD DeathStrokeSubjects: 2531 menAge: ≤74 (avg 64) yrMean baseline LDL-C:111 mg/dLMean baseline HDL-C:32 mg/dLMean baseline TG:161 mg/dLDuration of Type 2 DM:7 yrIntervention:Gemfibrozil 600 mg BID*P<0.001; †P=0.006; ‡P=0.07.Rubins HB, et al. N Engl J Med. 1999;341:
40 HOT Trial 48% Effect of Diastolic Target on CVD Events - 4 Years 24.4 3048%Risk Reduction24.420Events/1000Pt-Yrs18.61011.99.910.09.3<90<85<80<90<85<80Diabetic Patientsn=1,501, P=0.016Non-Diabetic Patientsn=18,790, P=NSLancet 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 HgLifestyle InterventionDiet (FFV, low-fat dairy, low Na, modest E to H)Weight lossExercise (30 minutes most days of the week)Smoking cessationYesQuarterly to semi-annual follow-upSBP <130 and DBP <80?ThiazideMonthly to quarterly follow-upNo-blockerCoronary DiseaseAlbuminuria/CVD Risk FactorsACE/ARBVirtually all two-drug combinations should include a thiazide diureticThe third drug could (should) be a calcium channel blockerIn the setting of kidney or heart disease, consider adding a furosemide BID or torsemideIn 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 AlbuminuriaMean baseline characteristicsAge: 55 yrBMI: 30Duration of DM: ~5.8 yrA1c: 8.6%Randomized to conventional or intensive therapyMean follow-up: 7.8 yrGaede 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 StudyConventionalIntensiveA1c, %~9.0~7.8Systolic BP mm Hg~148~132LDL chol mg/dL~130~75TG mg/dL~260~150Gaede 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) 60Intensive TherapyP=0.007Hazard Ratio=0.47 (95% CI, ; P=0.008)53%Conventional Therapy5040Primary Composite End Point (%)30The 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.20101224364860728496Months of Follow-upGaede 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: