Insulin Therapy in Type 2 Diabetes Current and Future Directions

1、Insulin Therapy in Type 2 Diabetes:Current and Future DirectionsIssues in the Management ofType 2 DiabetesType 2: Deterioration of beta cells over timeIncreasing prevalence with increasing risk factors, eg, obesityHyperglycemia affects morbidity, mortality, and resourcesTight glycemic control with i

2、nsulin may reduce costly complications30% to 40% of patients ultimately require insulinRegimen-related limitations with current insulin formulations and delivery systemsNewer semisynthetic insulins and delivery systems may improve compliance and achieve better glycemic control with less hypoglycemia

3、Prevalence of Type 2 Diabetes MellitusMMWR. 1997;46:1014-1018.Incidence of Type 2 Diabetes MellitusMMWR. 1997;46:1014-1018.Risk Factors for Type 2 DiabetesNonmodifiableGenetic factorsAgeEthnicityModifiableWeightPhysical activityTrend in Prevalence of Obesity*: NHANES DataKuczmarski RJ, et al. JAMA.

4、1994;272:205-211.*BMI 27.3 mg/m2 for women; 27.8 kg/m2 for menLink Between Obesity and Type 2 Diabetes:Nurses Health StudyColditz GA, et al. Ann Intern Med. 1995;122:481-486.Link Between Obesity and Type 2 Diabetes:Nurses Health Study (contd)Colditz GA, et al. Ann Intern Med. 1995;122:481-486.ADA Tr

5、eatment GuidelinesBiochemical Index NormalGoal Action SuggestedPreprandial glucose90 mg/dL80-120 mg/dL140 mg/dLBedtime glucose120 mg/dL100-140 mg/dL160 mg/dLHbA1c6%*8%*Depending on assay normsMedical Nutrition Therapy for Type 2 DiabetesDietImproved food choicesSpacing mealsIndividualized carbohydra

6、te contentModerate calorie restrictionExercisePharmacologic Therapy for Type 2 DiabetesSulfonylureas (glyburide, glipizide, glimepiride)Biguanides (metformin)Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose)Benzoic acid analogues (repaglinide)Thiazolidinediones (troglitazone, rosiglitazon

7、e, pioglitazone)Insulin (human insulin, insulin analogues)Treatment AlgorithmNonpharmacologic therapyMonotherapySulfonylureas/Benzoic acid analogueBiguanideAlpha-glucosidase inhibitorsThiazolidinedionesInsulinCombination therapyInsulinVery symptomaticSevere hyperglycemiaKetosisLatent autoimmune diab

8、etesPregnancyConsiderations in Pharmacologic Treatment of Type 2 DiabetesEfficacy (HbA1c lowering capacity)Mechanisms of action of drugsImpact on weight gainComplications/tolerabilityFrequency of hypoglycemiaCompliance/complexity of regimenCostTight Glycemic Control:Reducing the Risk of Complication

9、sEpidemiologic evidence in type 2 diabetes to link microvascular disease and hyperglycemia first suggested in DCCTType 2 diabetes studies: Veterans Affairs Cooperative Study on Type 2 Diabetes (VA CSDM), United Kingdom Prospective Diabetes Study (UKPDS), and Kumamoto trialIntensive blood glucose con

10、trol with insulin, sulfonylurea, or metformin reduced risk of micro- and macrovascular complicationsGlycemic threshold to prevent onset and progression of microvascular complications: HbA1c 6.5%, FBG 110 mg/dL, 2-hr postprandial glucose 180 mg/dLImprovement in HbA1c in the VA CSDMP vs. placebo in in

11、tensive treatment groupAbraira C, et al. Diabetes Care. 1995;18:1113-1123.VA CSDM: Results at EndpointBaselineEndpointP ValueHbA1c9.3%6.9%2 yearsIntensive treatment not associated with severe hypoglycemia, weight gain, hypertension, or dyslipidemiaKumamoto trial:Intensive insulin treatment reduced m

12、icrovascular complicationsEstablished glycemic threshold to prevent onset and progression of complicationsUKPDS:Diet therapy alone inadequate in two thirds of patientsPharmacologic therapy plus nutrition/exercise necessaryWeigh benefit:risk ratioNo threshold for HbA1c reduction in reducing complicat

13、ionsInsulin does not increase macrovascular diseaseEffectiveOnsetPeakDurationInsulin lispro10,000 patients with type 1 or type 2 diabetes1-year parallel group comparisons or 6-month crossovers (3 months on each insulin) studiesDosage regimen: insulin lispro 10 min before and soluble human insulin 30

14、 to 45 minutes before meals, with NPH or ultralente insulin as the basal insulin supplementStrategies for Insulin Therapy in Elderly PatientsInsulin therapy often considered a last resort in the elderlyTherapeutic goals:Relieve symptomsPrevent hypoglycemiaPrevent acute complications of hyperglycemia

15、Ways to facilitate insulin treatment:Simple dose schedulesPremixed preparationsImproved, more convenient delivery systemsCombination Therapy: Oral Agents Plus Insulin RationaleCombination of two agents with different mechanisms of actionMore convenient and may be saferSulfonylurea + InsulinBIDS ther

16、apy: bedtime insulin/daytime sulfonylureaUseful in patients early in course of diseaseMetformin + InsulinImproves insulin sensitivityAlpha glucosidase inhibitor (acarbose) + InsulinDecreases postprandial glycemiaThiazolidinediones + InsulinImproves insulin resistance, improves insulin action in peri

17、pheral tissuesReduces insulin requirementMeta-Analysis of Sulfonylurea/InsulinCombination TherapyJohnson JL, et al. Arch Intern Med. 1996;156:259-264.Comparison of Insulin RegimensAmong Oral Treatment FailuresYki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.Total Direct Costs of Type 2 Diabet

18、esRathman W. Drug Benefit Trends. 1998;10:24-27.Total Indirect Costs of Type 2 DiabetesRathman W. Drug Benefit Trends. 1998;10:24-27.Ideal Basal InsulinClosely mimic normal pancreatic basal insulin secretionNo distinct peak effectContinued effect over 24 hoursReduce nocturnal hypoglycemiaOnce-daily

19、administration for patient compliancePredictable absorption patternEffectiveOnsetPeakDurationInsulin lispro15 min1 hr3 hrRegular0.5-1 hr2-3 hr3-6 hrNPH/Lente2-4 hr7-8 hr10-12 hrUltralente4 hrVaries18-20 hrInsulin glargine*1-2 hrFlat/Predictable24 hr*InvestigationalPharmacokinetics of Current Insulin

20、 Preparations Compared With Insulin GlargineBarnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilmans The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.Structur

21、e of Insulin Glargine:A New Long-Acting Insulin AnalogueModifications to human insulin chainSubstitution of glycine at position A21Addition of two arginines at position B30Unique release pattern from injection siteCharacteristics of Insulin GlargineEuglycemic clamp studies vs. NPHSmooth continuous r

22、elease from injection siteLonger duration of actionContinued effect at end of 24-hour clamp studyNo differences in the absorption rate from arm, leg, or abdominal sites No inflammatory reactions at any of the injection sitesFlat insulin profileAs effective in lowering FPG levels as NPH insulin, with

23、 significantly reduced nocturnal hypoglycemiaBlood Glucose Profile of Insulin Glargine in Normal VolunteersOwens DR, et al. Diabetologia. 1998;41(suppl 1):A245.Exogenous Insulin Concentration of Insulin Glargine in Normal VolunteersOwens DR, et al. Diabetologia. 1998;41(suppl 1):A245.Efficacy of Ins

24、ulin Glarginein Type 1 and Type 2 DiabetesRaskin P, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0404.Rosenstock J, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0357.*PSafety of Insulin Glargine in Type 1 and Type 2 DiabetesType 1 DiabetesSimilar incidence of hypoglycemia

25、 between insulin glargine and NPH after 4 weeks of treatmentPattern of adverse events and injection site reactions also similarType 2 DiabetesNo difference in frequency of hypoglycemia from NPHNo change in body weightOther Long-Acting Insulin AnaloguesGlycemic objectives:Provide constant, reproducib

26、le supply of basal insulin Adequately suppress hepatic glucose productionNovoSol BasalFirst long-acting insulin analogueDiscontinued because of local inflammatory reactionsIn developmentDi-arginyl human insulin analogue (Gly, Arg)C16 fatty-acid-acylated analogueNeed for Novel Delivery Systems of Ins

27、ulinDisadvantages of conventional subcutaneous injection:DiscomfortInconvenienceSystemic deliveryInconsistent pharmacokineticsIrreversible after injectionInsulin pumps: too complex, limited experience and utility with type 2Insulin pen: beneficial but underutilizedSystems in clinical testingInhaled

28、formulationJet-injected systemsInsulin PumpCSII: uses portable infusion pump connected to an indwelling subcutaneous catheter to deliver short-acting insulinIIP shown to have significant advantages over multiple daily injectionsReduces glycemic variability, clinical hypoglycemia, weight gainExtreme

29、for routine practice but may be useful in special circumstancesNot currently available in the United StatesInsulin PumpInsulin PenBenefitsMore accurate dosing mechanisms Faster and easier than conventional syringesImproved patient attitude and complianceAdvantages of newer insulin pensLCD display to

30、 show dosage settingDosage settings change quickly and easilySafety button automatically resets after drug deliveryInsulin PenInhaled Insulin FormulationsGelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.Continuous Glucose SensorsWhen available, may provide only mechanical means of achieving “normal glucose homeostasisWill direct ins