Presentation on theme: "Effective Use of Insulin in Diabetes: Update for 2007"— Presentation transcript:
1Effective Use of Insulin in Diabetes: Update for 2007 Thomas M. Flood, MDDirectorGeorgia Center for DiabetesAtlanta, Georgia
2Key Question?How comfortable are you with initiating insulin therapy in your patient population?Completely comfortableSomewhat comfortableSlightly comfortableNot comfortable at allUse your keypad to vote now!
3Faculty DisclosureDr Flood has no relevant financial relationships with any commercial interests to disclose.
4Learning Objectives State current management goals for diabetes Identify barriers to optimal use of insulin, and how to overcome themDiscuss the roles of short-, intermediate-, and long-acting insulins in the management of diabetes
5A1C Targets Suggested by Different Organizations Optimal target: A1C <6% (normal range)OrganizationA1C Target (%)AACE<6.5EASDADA<7 (general)<6* (individual patient)*As close to normal (<6%) without significant hypoglycemia.AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes.
6? Key Question What percentage of patients with diabetes achieve the AACE goal of A1C <6.5%?25%35%55%75%Use your keypad to vote now!
7National average = 67% above goal (A1C 6.5%) State of Diabetes in America: Blood Sugar Control Across the United States as Measured by A1CNational average = 67% above goal (A1C 6.5%)WA68.4ME27.2MT55.2ND29.7MN59.3OR64.2VTVT = 26.7NH = 20.4MA = 29.5CT = 28.4RI = 29.5NJ = 67.3DE = 66.4MD = 68.1ID63.3NY71.1NHSD24.6W24.2IWY63.0MI65.4MACTRIIA58.9PA70.9NE56.5NV67.3OH71.7NJIL72.6IN66.4MDUT72.4CO67.1WV69.5DECA34.5VA67.7KS67.0MO66.2KY66.8TN65.6NC65.7OK65.6AZ67.3AR69.6NM68.6SC66.3MS72.8AL71.3GA69.3TX67.7LA71.3FL63.9N >157,000Top 10 HighestAACE. State of Diabetes in America. May Available at:American Association of Clinical Endocrinologists. State of Diabetes in America. Report presented at: American Association of Clinical Endocrinologists 14th Annual Meeting and Clinical Congress; Washington, DC; May 18,
8Diabetes Demographics in the United States Population Aged ≥20 YearsPhysician-Diagnosed Diabetes (%)Undiagnosed Diabetes (%)Male18.104.22.168.3Female22.214.171.124White5.06.22.8Black8.6126.96.36.199Mexican9.7188.8.131.52Total7.33.0Adapted from: National Center for Health Statistics. Health, United States, With Chartbook on Trends in the Health of Americans. Hyattsville, Md: 2006.
9No A1C Threshold in Type 2 Diabetes Epidemiologic Data From the UKPDS80Myocardial infarctionMicrovascular end points60AACE GoalAdjusted Incidence per 1000 Person-Years (%)4020?567891011Updated Mean A1C (%)UKPDS = United Kingdom Prospective Diabetes Study.Stratton IM et al. BMJ. 2000;321:
10Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000 NHANES , n = 37048.2%5044.3%P <.00137.0%4035.8%33.9%29.0%30Patients (%)20105.2%7.3%A1C <7%BP <130/80 mm HgTC <200 mg/dLGood control**Achieved all 3 indicated goals.BP = blood pressure; NHANES = National Health and Nutrition Examination Survey; TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:
11Stages of Type 2 Diabetes: Criteria for Advancing to Next Stage? A1C not at target: 7.0%100Monotherapy75Combination oraltherapyβ-Cell Function (% β)50Insulin25Type 2DiabetesPhase IType 2DiabetesPhase IIPhase III-12-10-6-2261014Years From DiagnosisBased on data of UKPDS 16.UKPDS Group. Diabetes. 1995;44:
12Stepwise Management of Type 2 Diabetes +Diet andexercise+ Oral monotherapy+ Oral combination+ Oral combo + insulin+ InsulinBiggest Clinical Hurdle?Adapted from Williams G. Lancet. 1994;343:
13? Key Question What is the approximate amount that A1C can be lowered through use of oral agents?1%2%3%4%Use your keypad to vote now!
14Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C AcarboseInsulin-0.5-1.0-1.5-2.0NateglinideReduction in A1C (%)Glipizide GITSGlimepirideRepaglinidePioglitazoneMetforminRosiglitazoneSitagliptinPrecose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23: ; Garber AJ et al. Am J Med. 1997;102: ; Goldberg RB et al. Diabetes Care. 1996;19: ; Hanefeld M et al. Diabetes Care. 2000;23: ; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86: ; Simonson DC et al. Diabetes Care. 1997;20: ; Wolfenbuttel BH, van Haeften TW. Drugs. 1995;50:
15UKPDS: Early Initiation of Insulin Therapy Improves A1C Control Conventional therapyInsulin therapySulfonylurea ± insulin therapy987A1C (%)ULN = 6.2%65123456Years From RandomizationULN = upper limit of A1C nondiabetic range.Wright A et al. Diabetes Care. 2002;25:
16Clinical Inertia: “Failure to Advance Therapy When Required” Last A1C Value Before Abandoning Treatment109.6%Mean A1C at Last Visit (%)9.1%98.6%8.8%8ADA Goal7SulfonylureaDiet/ExerciseCombinationMetformin2.5 Years2.9 Years2.2 Years2.8 YearsBrown JB et al. Diabetes Care. 2004;27:
17? Key Question What are the barriers for your patients with type 2 diabetes regarding initiation ofinsulin therapy?Concern that insulin use is “forever”Fear of injectionEquating insulin use with worsening diabetes and complicationsFear of weight gainUse your keypad to vote now!
18Patient Barriers to Insulin Use: Perception vs Reality Failing oral therapy58% of patients believe using insulin means they have failed OAD therapyOAD failure is due to progressive nature of type 2 diabetes; insulin is best agent to control diseaseNeedle phobiaFear associated with early experiencesCurrent needles considered painless; easy-to-use injection systems are availableFear of complicationsCommon association of insulin with diabetic complicationsComplications are due to uncontrolled, progressive disease; insulin actually results in reduction of vascular damageOAD = oral antidiabetic drug.Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:
19Clinician Barriers to Insulin Use: Perception vs Reality Hypoglycemia is prevalent with insulin useSevere hypoglycemia is very uncommon in patients with type 2 diabetes, occurring at 10% the rate in patients with type 1 diabetesInsulin use increases atherosclerosisStudies indicate no exacerbation of cardiovascular diseaseThere is weight gain with insulin useWeight gain is modest and can be controlled with diet and exercisePatients have a negative attitude regarding insulin useInsulin is a “positive” approach to achieving glycemic controlDouek IF et al. Diabet Med. 2005;22: ; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65; Malmberg K et al. BMJ. 1997;314: ; Romano G et al. Diabetes. 1997;46: ; UKPDS Group. Lancet. 1998;352:
20Information and Patient Education Links for Healthcare Professionals American Association of Diabetes Educators (www.diabeteseducator.org)American Association of Clinical Endocrinologists (www.aace.com)American Diabetes Association (www.diabetes.org)International Diabetes Federation (www.idf.org)National Diabetes Education Initiative (www.ndei.org)National Diabetes Education Program (ndep.nih.gov)National Institute of Diabetes and Digestive and Kidney Diseases (www2.niddk.nih.gov)
21Next Steps…What do we do for the patient who has failed on 1 or 2 oral agents?
22Basal Insulin Therapy Usual first step when beginning insulin therapy Continue OAD and add basal insulin to optimize FPGA1C of up to 9.0% often brought to goal by addition of basal insulin therapy to OADsEasy and safe: patient-directed treatment algorithms with small risk of serious hypoglycemiaADA and EASD recommended: “Although 3 OADs can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense”Basal Insulin TherapyThe addition of basal insulin therapy to oral antidiabetic drugs (OADs) is the usual first step in transitioning from OAD therapy.The goal is to optimize fasting plasma glucose (FPG) values and reduce glucolipotoxicity.In many cases, A1C levels of up to 9.0% can often be brought to goal using basal insulin therapy.There are several patient-directed treatment algorithms available, which make titration to effective doses easy for the patient to manage.There is a small risk of hypoglycemia associated with basal insulin therapy.ReferencesAmerican Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2006;29(suppl 1): S4-S42.American Association of Clinical Endocrinologists. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference recommendations: Position statement. Available at: Accessed July 3, 2006.Category: Insulin TherapyKeywords: basal, FPG, A1C, initiate, goals, insulinFPG = fasting plasma glucose.ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement. Available at:Nathan DM et al. Diabetes Care. 2006;29:
23Rationale for Basal Insulin Therapy: Insulin and Glucose Patterns NormalT2DMGlucoseInsulin40012010030080μU/mLmg/dL2006040100206:0010:0014:0018:0022:002:006:006:0010:0014:0018:0022:002:006:00BLDBLDTimeTimeB = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.Polonsky KS et al. N Engl J Med. 1988;318:
25Idealized Profiles of Human Insulin and Basal Insulin Analogs NPHPlasma Insulin LevelsDetemirGlargine0:002:004:006:008:0010:0012:0014:0016:0018:0020:0022:0024:00TimePlank J et al. Diabetes Care. 2005;28: ; Rave K et al. Diabetes Care. 2005;28: ; Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY: Martin Dunitz; 2003:
26Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)–Aspart Mix (70/30) 4:0016:0020:0024:00BreakfastLunchDinnerInsulin Action8:0012:00TimeGlucose levels Insulin levelsAdapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:
27Open-Label, Twice-Daily Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n = 549)Exenatide5 μg bid 1st 4 weeks, then 10 μg bidInsulin Glargine10 U/d, titrated to target FPG <100 mg/dL240240220220200200Mean end of study dose was 25 U compared with 47 U in the Treat-to-Target trial.Least-squares mean (SE) data for self-monitored blood glucose concentrations at baseline and week 26 are shown for the exenatide and insulin glargine groups. In a 24-hour period, data were collected just before each meal (fasting, pre–midday meal, pre– evening meal), 2 hours after each meal (post–morning meal, post–midday meal, post– evening meal), and at 3:00 a.m. At week 26, the exenatide group had higher mean values for blood glucose levels at fasting (P <0.001), before lunch (P = 0.023), before dinner (P = 0.006), and at 3:00 a.m. (P <0.001), but the group had lower glucose levels after morning (P <0.001) and evening (P <0.001) meals than the group receiving insulin glargine.Heine RJ et al. Ann Intern Med. 2005;143:180180Blood Glucose (mg/dL)160160140140120Baseline (week 0)120Baseline (week 0)Endpoint (week 26)100100Endpoint (week 26)PrebreakfastPrelunchPredinner3 AMPrebreakfastPrelunchPredinner3 AMBoth medications lowered A1C from 8.2% to 7.1% from baselineWeight change: exenatide –2.3 kg, glargine +1.8 kgNausea: exenatide 57.1%, glargine 8.6%Heine RJ et al. Ann Intern Med. 2005;143:
28Steps in Transition From Basal to Basal-Bolus Insulin Therapy in T2DM Glargine, Detemir,or NPH HSWeekly titration based on FPGAll oral agents continuedSTEP 1AbovetargetAdd insulinMain mealSTEP 2AbovetargetAdd insulinNext largest mealSTEP 3AbovetargetAdd insulinLast mealSTEP 4Above target:A1C >7.0%FPG >110 mg/dLA1C <7.0%, FPG <110 mg/dLHS = at bedtime.Adapted with permission from Karl DM. Curr Diab Rep. 2004;4:
30Case Study: Initiating Insulin Therapy 60-year-old man: 10-year history of T2DM and hypertensionCurrent T2DM medications: metformin 1000 mg bid, rosiglitazone 8 mg AM, and glimepiride 8 mg qdHypertension medications: 40 mg lisinopril, 10 mg amlodipine, mg HCTZDyslipidemia medication: 10 mg atorvastatinPhysical exam: weight = 245 lb (10-lb increase); height = 6’0”; BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm HgLaboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL; LDL = 90 mg/dLA1C = 8.9%; plasma glucose in the office = 198 mg/dLCreatinine 1.1 mg/dL, normal LFTsHCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function tests; BMI = body mass index.
31Case Study (cont’d) Patient agrees to basal insulin therapy, however: Expresses feelings of failure at inability to control glycemia with OADsDisplays anxiety about injectionsYou explain the progressive nature of diabetes:Convey that insulin injections are the best way to achieve glycemic controlDescribe injection options (“painless” needles, injector pens, etc)Indicate that you and the patient will be a “team” in getting to the A1C goal
32? Decision Point Which insulin would you use? NPH at bedtime Glargine once dailyTwice-daily premixedDetemir at bedtimeUse your keypad to vote now!
33Treat-to-Target Trial: Oral Agents + Glargine or NPH at Bedtime Patients (n = 756) with inadequate glycemic control (A1C >7.5%) taking 1 or 2 oral agentsStarted with 10 U/d bedtime basal insulin and adjusted weekly to target FPG 100 mg/dL:Mean self-monitored FPG values from preceding 2 days (mg/dL)Increase of insulin dosage(U/d)≥1808140 – 1806120 – 1404100 – 1202Exceptions were no increase in dosage if plasma-referenced glucose <72 mg/dl was documented at any time in the preceding week, and in addition to no increase, small insulin dose decreases (2 – 4 units/day per adjustment) were allowed if severe hypoglycemia (requiring assistance) or plasma-referenced glucose <56 mg/dl were documented in the preceding week.11Riddle MC et al. Diabetes Care. 2003;26:Hermansen K et al. Diabetes Care. 2006;29: ; Riddle MC et al. Diabetes Care. 2003;26:
34Treat-to-Target Trial: Oral Agents + Glargine or NPH at Bedtime (n=756): Efficacy Results Patients (n=756) with inadequate glycemic control (A1C >7.5%) on 1 or 2 oral agentsRandomized to bedtime glargine or NPHTarget FPG 100 mg/dLAdjustments made once weekly; therapy is advanced unless hypoglycemia present*In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively, by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks.Riddle MC et al. Diabetes Care. 2003;26:
35Treat-to-Target Trial: Timing and Frequency of Hypoglycemia Hypoglycemia by Time of DayBasal insulinInsulin glargine350**NPH insulin300*250*Hypoglycemia Episodes (PG 72 mg/dL)200***15010050B L D20:0022:0024:002:004:006:008:0010:0012:0014:0016:0018:0020:00Time*P <.05 (between treatment).Riddle MC et al. Diabetes Care. 2003;26:
36Detemir vs NPH Insulin in T2DM (n = 476) 40035030025020015010050A1C (%)10.09.08.07.06.0DetemirNPHHypoglycemia Events*-2481216202424812162024Study WeekStudy Week*All reported events, including symptoms only.Hermansen K et al. Diabetes Care. 2006;29:
37Case Study (cont’d) 10 U glargine is added to OADs Patient is sent home with the “2, 4, 6, 8 algorithm” with a target FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be used with detemir2FPG (mg/dL) Insulin Dose (U/d)>Alternative strategy: increase basal insulin dose by 2 units every 3 days until FPG 100 mg/dL*3*Certain populations (children, pregnant women, and the elderly) require special considerations.Riddle MC et al. Diabetes Care. 2003;26:Hermansen K et al. Diabetes Care. 2006;29:Davies M et al. Diabetes. 2004;53(suppl 2):1980.
38Case Study (cont’d) Patient is seen 1 month later FPG still above 200 mg/dL, using up to 30 U dailyPatient is frustrated and feels the insulin does not work
39? Decision Point What do you do now? Keep increasing the insulin dose Go to twice-daily premixedSwitch to exenatideSend patient for gastric bypass consultUse your keypad to vote now!
40Treat-to-Target Trial 50Units45Total Daily Dose (U)42403733283021201010123456781012151821N = 756.Riddle MC et al. Diabetes Care. 2003;26:Weeks in Study
41Case Study (cont’d)Patient is taking 75 U with FPG controlled (<100 mg/dL to rarely >110 mg/dL) since last visit 4 months agoPatient’s last A1C = 6.9%, monitoring occasional postprandial blood sugarsPatient finds insulin injections painless and after speaking with you, feels that he is now a partner in his therapy program
42Case Study (cont’d)Over the next 3 years, patient seen for routine follow-up every 3 to 4 monthsRemains medically stable, with A1C values 6.5% to 7.2%3.25 years after adding basal insulin glargine, A1C has increased to 8.2%, however, FPG checks remain <120 mg/dL
43? Decision Point What do you do now? Increase glargine Switch to twice-daily premixedSwitch to 4-shot basal-bolus programIncrease monitoring to AC and HS, and have patient report after 2 weeksUse your keypad to vote now!AC = before meals; HS = at bedtime.
44Case Study (cont’d)Because the patient’s FPGs are good and post-prandial glucose levels are high, the decision is made to switch to twice-daily premixed insulinThe patient is encouraged to increase daily monitoring to adjust insulin dose
45At Lower A1C Levels, PPG Contributes More to Overall A1C Than FPG Contribution (%)12345A1C QuintilePPG = postprandial glucose.Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:
46Plasma Glucose (mg/dL) Prandial Excursions Are Evident, Especially Around a Single Key Meal: Insulin Glargine vs Premixed (n = 209)35030025020015010050Premixed†GlargineBaselinePlasma Glucose (mg/dL)*****Week 28BBB90BLL90BDD90Bed3 AMTime of DayTotal units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30)*Denotes statistically significant difference between treatment groups at specific times.†Premixed = BIAsp 70/30.Raskin P et al. Diabetes Care. 2005;28:
47Case Study (cont’d) Daily Blood Glucose Diary 147 110 153 185 57 138 Week EndingMarch 24BreakfastLunchDinnerMSMiddle of NightDoseBlood SugarMonday14711015318557Tuesday13811217016448Wednesday14090155205Thursday16610513421360FridaySaturdaySunday
48Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)–Aspart Mix (70/30) 4:0016:0020:0024:00BreakfastLunchDinnerInsulin Action8:0012:00TimeGlucose levels Insulin levelsAdapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:
49Idealized Profiles: Rapid-Acting Insulin Analogs Inhaled insulin*Regular insulinPlasma Insulin Levels0:002:004:006:008:0010:0012:0014:0016:0018:0020:0022:0024:00Time*Inhaled dry human insulin (Exubera®) powderRosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY: Martin Dunitz; 2003: ; Plank J et al. Diabetes Care. 2005; 28: ; Rave K et al. Diabetes Care. 2005;28:
50Case Study (cont’d)Decision is made to switch to basal-prandial therapy to reduce hypoglycemia and postprandial highs60% of patient’s total daily insulin dose is given as basal insulin – 54 U glargine qhs titrated to FPG mg/dLBefore the main meal, a rapid-acting analog is added: glulisine, initiated at 5 units, up-titrated using a treat-to-target algorithmPatient continues to self-monitor glucose
51Meal Insulin: Rapid-Acting Analogs (Lispro, Aspart, Glulisine) vs Regular Analog insulin10Timing offood absorbed8RHI6Insulin Activity42123456789101112HoursRHI = regular human insulin.Adapted with permission from Howey DC et al. Diabetes. 1994;43:
52Advantages of Rapid-Acting Analogs Short duration of action—fewer between-meal “hypos” than regular insulinFlexible mealtime dosingMore consistent kineticsDay to dayAcross anatomical sitesWith large dosesSlightly faster onset of glulisine action (compared to lispro) in obese and morbidly obese subjects (independent of BMI)*Adapted from Hirsch IB. N Engl J Med. 2005;352:Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:*Heise T et al. Diabetes. 2005;54(suppl 1):A145.
53? Decision Point The best time to use a rapid-acting insulin analog is:Before a mealAfter a mealEither works wellUse your keypad to vote now!
54Significant reduction in A1C with pre- and postmeal glulisine Pre- and Postmeal Efficacy of Insulin Glulisine vs Regular Human InsulinSignificant reduction in A1C with pre- and postmeal glulisineP <.05P <.05P <.05BaselineEndpointEfficacy of Algorithmic Basal-Prandial Insulin Analog TitrationAt week 24, the A1C was significantly reduced in both the ALG and Carb Count groups (P<0.0001).ReferenceBergenstal R, Johnson M, Powers M, Wynne A, Vlajnic A, Hollander A. Using a simple algorithm (ALG) to adjust mealtime glulisine (GLU) based on preprandial glucose patterns is a safe and effective alternative to carbohydrate counting (Carb Count). Diabetes. 2006;55(suppl 1):A105.Abstract 441P.Significant A1C reduction with premeal glulisine compared to premeal human insulinGarg SK et al. Endocr Pract. 2005;11:11-17; Garg SK et al. Poster presented at ADA 64th Annual Scientific Sessions, June 4-8, 2004, Diabetes. 7:529P.
55Case Study (cont’d)At 6-month follow-up patient is doing well with 70 U glargine and 10 U to 17 U glulisine at supperActual dose adjusted byMeal carbohydrate contentActivityInsulin supplement of additional 1 U for every 25 mg/dL above 130 mg/dL (prandial glucose)A1C = 6.3%He feels well, has infrequent “hypos,” and is pleased with his blood glucose control
58PCE Takeaways: Basal-Prandial Insulin Replacement An effective insulin treatment strategy provides both basal and postprandial insulin coverageInitially, prandial insulin may be needed only at the largest meal of the day, with coverage at other meals added based on prandial glucose levelsRapid-acting insulin analogs closely match normal mealtime insulin patternsPrandial Insulin Replacement: SummaryAn effective strategy for the treatment of patients with type 2 diabetes is the use of an insulin regimen that provides both basal and postprandial insulin coverage.Initially, prandial insulin may be needed only at the largest meal of the day. Over time, premeal glucose levels may indicate the need for administration of prandial insulin at more meals.Rapid-acting insulin analogs, which closely match normal mealtime insulin patterns compared with regular human insulin, are an effective option.A simple algorithm based on premeal blood glucose levels can been shown to be a safe and effective way to titrate prandial insulin doses.
59Key Question?How much more comfortable do you now feel you will be initiating insulin therapy in your patient population?Much more comfortableSomewhat comfortableSlightly comfortableNot comfortable at allUse your keypad to vote now!