Presentation on theme: "Insulin Therapy in Type 2 Diabetes: Current and Future Directions"— Presentation transcript:
1 Insulin Therapy in Type 2 Diabetes: Current and Future Directions
2 Issues in the Management of Type 2 Diabetes Type 2: Deterioration of beta cells over timeIncreasing prevalence with increasing risk factors, eg, obesityHyperglycemia affects morbidity, mortality, and resourcesTight glycemic control with insulin 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 Mellitus MMWR. 1997;46:
4 Incidence of Type 2 Diabetes Mellitus MMWR. 1997;46:
5 Risk Factors for Type 2 Diabetes NonmodifiableGenetic factorsAgeEthnicityModifiableWeightPhysical activity
6 Trend in Prevalence of Obesity*: NHANES Data *BMI 27.3 mg/m2 for women; 27.8 kg/m2 for menKuczmarski RJ, et al. JAMA. 1994;272:
7 Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study Colditz GA, et al. Ann Intern Med. 1995;122:
8 Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study (cont’d) Colditz GA, et al. Ann Intern Med. 1995;122:
9 ADA Treatment Guidelines Biochemical Index Normal Goal Action SuggestedPreprandial glucose <90 mg/dL mg/dL <80 or >140 mg/dLBedtime glucose <120 mg/dL mg/dL <100 or >160 mg/dLHbA1c <6%* <7% >8%*Depending on assay norms
10 Medical Nutrition Therapy for Type 2 Diabetes DietImproved food choicesSpacing mealsIndividualized carbohydrate contentModerate calorie restrictionExercise
13 Considerations in Pharmacologic Treatment of Type 2 Diabetes Efficacy (HbA1c lowering capacity)Mechanisms of action of drugsImpact on weight gainComplications/tolerabilityFrequency of hypoglycemiaCompliance/complexity of regimenCost
14 Tight Glycemic Control: Reducing the Risk of Complications Epidemiologic 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 control 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/dL
15 Improvement in HbA1c in the VA CSDM P<0.001 vs. placebo in intensive treatment groupAbraira C, et al. Diabetes Care. 1995;18:
16 VA CSDM: Results at Endpoint Baseline Endpoint P ValueHbA1c 9.3% 6.9% <0.001Fasting serum glucose 206 mg/dL 118 mg/dL <0.001Insulin dose 22.9 U UBlood pressure* 136/81 mmHg 137/80 mmHgTotal cholesterol* 5.9 mg/dL 5.2 mg/dL 0.003HDL cholesterol* 1.1 mg/dL 1.0 mg/dLLDL cholesterol* 3.5 mg/dL 3.4 mg/dLTriglycerides* 2.3 mg/dL 2.0 mg/dL 0.06*Results at 2 yearsAbraira C, et al. Diabetes Care. 1995;18:
17 The Kumamoto Trial: Effects of Conventional vs The Kumamoto Trial: Effects of Conventional vs. Intensive Insulin TherapyOhkubo Y, et al. Diabetes Res Clin Pract. 1995;28:
18 UKPDS: Effect of Intensive Therapy on Glycemia UKPDS Group. Lancet. 1998;352:
19 UKPDS 10-Year Cohort Data: Reductions With Intensive vs UKPDS 10-Year Cohort Data: Reductions With Intensive vs. Conventional TherapyUKPDS Group. Lancet. 1998;352:
20 Summary of Key Findings VA CSDM:Glycemic control achievable with intensive insulin treatment: control maintained >2 yearsIntensive treatment not associated with severe hypoglycemia, weight gain, hypertension, or dyslipidemiaKumamoto trial:Intensive insulin treatment reduced microvascular 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 complicationsInsulin does not increase macrovascular disease
21 Pharmacokinetics of Current Insulin Preparations EffectiveOnset Peak DurationInsulin lispro <15 min 1 hr 3 hrRegular hr 2-3 hr 3-6 hrNPH/Lente 2-4 hr 6-12 hr hrUltralente 4-8 hr Varies hrBarnett AH, Owens DR. Lancet. 1997;349: White JR, et al. Postgrad Med. 1997;101:58-70.Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:
22 Clinical Efficacy of Insulin Lispro Worldwide clinical trials of insulin lispro in >10,000 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 to 45 minutes before meals, with NPH or ultralente insulin as the basal insulin supplement
23 Strategies for Insulin Therapy in Elderly Patients Insulin therapy often considered a last resort in the elderlyTherapeutic goals:Relieve symptomsPrevent hypoglycemiaPrevent acute complications of hyperglycemiaWays to facilitate insulin treatment:Simple dose schedulesPremixed preparationsImproved, more convenient delivery systems
24 Combination Therapy: Oral Agents Plus Insulin RationaleCombination of two agents with different mechanisms of actionMore convenient and may be saferSulfonylurea + InsulinBIDS therapy: 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 peripheral tissuesReduces insulin requirement
25 Meta-Analysis of Sulfonylurea/Insulin Combination Therapy Johnson JL, et al. Arch Intern Med. 1996;156:
26 Comparison of Insulin Regimens Among Oral Treatment Failures Yki-Jarvinen H, et al. N Engl J Med. 1992;327:
27 Total Direct Costs of Type 2 Diabetes Rathman W. Drug Benefit Trends. 1998;10:24-27.
28 Total Indirect Costs of Type 2 Diabetes Rathman W. Drug Benefit Trends. 1998;10:24-27.
29 Ideal Basal InsulinClosely mimic normal pancreatic basal insulin secretionNo distinct peak effectContinued effect over 24 hoursReduce nocturnal hypoglycemiaOnce-daily administration for patient compliancePredictable absorption pattern
30 Pharmacokinetics of Current Insulin Preparations Compared With Insulin Glargine EffectiveOnset Peak DurationInsulin lispro <15 min 1 hr 3 hrRegular hr 2-3 hr 3-6 hrNPH/Lente 2-4 hr 7-8 hr hrUltralente 4 hr Varies hrInsulin glargine* 1-2 hr Flat/Predictable 24 hr*InvestigationalBarnett AH, Owens DR. Lancet. 1997;349: White JR, et al. Postgrad Med. 1997;101:58-70.Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.
31 Structure of Insulin Glargine: A New Long-Acting Insulin Analogue Modifications to human insulin chainSubstitution of glycine at position A21Addition of two arginines at position B30Unique release pattern from injection site
32 Characteristics of Insulin Glargine Euglycemic clamp studies vs. NPHSmooth continuous release from injection siteLonger duration of actionContinued effect at end of 24-hour clamp studyNo differences in the absorption rate from arm, leg, or abdominal sitesNo inflammatory reactions at any of the injection sitesFlat insulin profileAs effective in lowering FPG levels as NPH insulin, with significantly reduced nocturnal hypoglycemia
33 Blood Glucose Profile of Insulin Glargine in Normal Volunteers Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.
34 Exogenous Insulin Concentration of Insulin Glargine in Normal Volunteers Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.
35 Efficacy of Insulin Glargine in Type 1 and Type 2 Diabetes Raskin 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.
36 Safety of Insulin Glargine in Type 1 and Type 2 Diabetes Similar incidence of hypoglycemia 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 weight
37 Other Long-Acting Insulin Analogues Glycemic objectives:Provide constant, reproducible supply of basal insulinAdequately 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 analogue
38 Need for Novel Delivery Systems of Insulin Disadvantages 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 formulationJet-injected systems
39 Insulin 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 for routine practice but may be useful in special circumstancesNot currently available in the United States
41 Insulin Pen Benefits Advantages of newer insulin pens More accurate dosing mechanismsFaster and easier than conventional syringesImproved patient attitude and complianceAdvantages of newer insulin pensLCD display to show dosage settingDosage settings change quickly and easilySafety button automatically resets after drug delivery
43 Inhaled Insulin Formulations Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.
44 Continuous Glucose Sensors When available, may provide only mechanical means of achieving “normal” glucose homeostasisWill direct insulin delivery automatically on demand (“closed loop”)One technology uses reverse iontophoresis to noninvasively extract and measure glucose levelsTechnical challenge to develop
45 Conclusions Type 2 diabetes: gradual deterioration of glycemic control Significant morbidity and mortality; tight glycemic control reduces risk of complicationsEarlier institution of insulin may help attain initial glycemic controlObjectives of insulin therapy:Achieve normal fasting glucose levelsAchieve normal postprandial glucose levelsMinimize hypoglycemiaIntensive insulin therapy should:Provide good glycemic controlProduce little hypoglycemiaImprove lipid profileReduce risks and costs of treating complications
46 Conclusions (cont’d) New delivery systems: Reduce limitations of conventional insulin syringesImprove patient compliance and disease managementNew long-acting insulin analogues (eg, insulin glargine):Produce flat insulin profile with no peaksAllow once-daily administrationSignificantly reduce nocturnal hypoglycemia