Insulin Therapy in Type 2 Diabetes:Current and Future Directions

Issues 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 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

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 activity

Trend in Prevalence of Obesity*: NHANES DataKuczmarski RJ, et al. JAMA. 1994;272:205-211.*BMI 27.3 mg/m2 for women; 27.8 kg/m2 for men

Link 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 Treatment GuidelinesBiochemical Index NormalGoal Action Suggested

Preprandial glucose

Medical Nutrition Therapy for Type 2 DiabetesDietImproved food choicesSpacing mealsIndividualized carbohydrate contentModerate calorie restrictionExercise

Pharmacologic Therapy for Type 2 DiabetesSulfonylureas (glyburide, glipizide, glimepiride)Biguanides (metformin)Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose)Benzoic acid analogues (repaglinide)Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone)Insulin (human insulin, insulin analogues)

Treatment AlgorithmNonpharmacologic therapyMonotherapySulfonylureas/Benzoic acid analogueBiguanideAlpha-glucosidase inhibitorsThiazolidinedionesInsulinCombination therapyInsulinVery symptomaticSevere hyperglycemiaKetosisLatent autoimmune diabetesPregnancy

Considerations in Pharmacologic Treatment of Type 2 DiabetesEfficacy (HbA1c lowering capacity)Mechanisms of action of drugsImpact on weight gainComplications/tolerabilityFrequency of hypoglycemiaCompliance/complexity of regimenCost

Tight Glycemic Control:Reducing the Risk of ComplicationsEpidemiologic 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

Improvement in HbA1c in the VA CSDMP

VA CSDM: Results at EndpointBaselineEndpointP Value

HbA1c9.3%6.9%

The Kumamoto Trial: Effects of Conventional vs. Intensive Insulin TherapyOhkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.

UKPDS: Effect of Intensive Therapy on GlycemiaUKPDS Group. Lancet. 1998;352:837-853.

UKPDS 10-Year Cohort Data: Reductions With Intensive vs. Conventional TherapyUKPDS Group. Lancet. 1998;352:837-853.

Summary of Key FindingsVA 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

EffectiveOnsetPeakDuration

Insulin lispro

Clinical Efficacy of Insulin LisproWorldwide 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

Strategies for Insulin Therapy in Elderly PatientsInsulin 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

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

Meta-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 DiabetesRathman 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 administration for patient compliancePredictable absorption pattern

EffectiveOnsetPeakDuration

Insulin lispro

Structure 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 site

Characteristics of Insulin GlargineEuglycemic 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 sites No inflammatory reactions at any of the injection sitesFlat insulin profileAs effective in lowering FPG levels as NPH insulin, with significantly reduced nocturnal hypoglycemia

Blood 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 Insulin 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.*P=0.0001

Safety of Insulin Glargine in Type 1 and Type 2 DiabetesType 1 DiabetesSimilar 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

Other Long-Acting Insulin AnaloguesGlycemic objectives:Provide constant, reproducible 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 analogue

Need for Novel Delivery Systems of InsulinDisadvantages 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

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

Insulin Pump

Insulin PenBenefitsMore accurate dosing mechanisms Faster 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

Insulin Pen

Inhaled 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 insulin delivery automatically on demand (closed loop)One technology uses reverse iontophoresis to noninvasively extract and measure glucose levelsTechnical challenge to develop

ConclusionsType 2 diabetes: gradual deterioration of glycemic controlSignificant morbidity and mortality; tight glycemic control reduces risk of complicationsEarlier institution of insulin may help attain initial glycemic control Objectives 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

Conclusions (contd)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