6All patients with type 1 diabetes need insulin treatment permanently, unless they receive an islet or whole organ pancreas transplant; many patients with type 2 diabetes will require insulin as their beta cell function declines over time.
7Indications for insulin therapy unexplained recent weight loss (irrespective of the initial weight),a short history with severe symptoms,the presence of moderate to heavy ketonuria.pregnancy
8Type 2 DMPatient with persistent elevated FPG leves ( mg/dl) or ketonuria or ketonemiaFPG more than 300 mg/dl with polyuria, polydipsia and weight lossGestational diabetesUncontrolled diabetes with oral agentsPhysician-patient option wish to receive insulin as initial therapyWasting stateLatent autoimmune diabetes in adultPost MIRenal failureAllergy or serious reaction to oral agents
10Types of insulin Insulin glargine : No real advantage with regard to A1CLower fasting blood glucose and fewer hypoglycemic episodesDo not mix with other insulin
11Glargine: 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
12Characteristics 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
15Insulin detemirIts duration of action appears to be substantially shorter than that of insulin glargine,Compare to NPH insulin detemir may be associated with slightly less nocturnal hypoglycemia and weight gain
16Very-rapid-acting insulin lispro,aspartglulisineOnset of action within 5 to15 Peak action at 30 to 90 Duration of action of two to four hours.
17Clinical Efficacy of Insulin Lispro Worldwide clinical trials of insulin lispro in >10,000 patients with type 1 or type 2 diabetesDosage 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
18Advantages of very rapid acting to regular decreases the postprandial rise in blood glucosereduce the frequency of hypoglycemiaIt is more convenient because it can be injected immediately before mealsNo difference in A1CNeed to increase in the dose of NPH when a patient is switched from regular insulin to a very-rapid-acting insulin
19The teratogenicity and long term safety profile of rapid-acting insulins in pregnancy are unknown, although many diabetologists do prescribe very-rapid-acting insulins during pregnancy.
20CHOICE OF INSULIN REGIMEN The basic requirements are :Baseline dose of insulin (whether an intermediate or long-acting insulin or given via CSII) plusAdjustable doses of pre-meal rapid-acting insulin (regular) or very-rapid-acting insulin analogs (lispro, aspart, or glulisine).
21Method of Insulin Preparation Conventional insulin therapyIntensive insulin therapy:MSICSII
25Getting startedStart on a total daily dose of 0.2 to 0.4 units of insulin per kg per day, although most will ultimately require 0.6 to 0.7 units per kg per day.One-half of the total dose as a basal insulin (2/3 in the morning 1/3 in the bed timeThe remainder is given as rapid or very rapid-acting insulin, divided before meals.The pre-meal dosing is determined by the usual meal size and content, as well as activity and exercise pattern.
33Insulin PumpCSII: uses portable infusion pump connected to an indwelling subcutaneous catheter to deliver short-acting insulin
34MSI or CSII Same efficacy, Same frequency of hypoglycemic events, Same impact on quality of life for most patients
35MSI CSIIFor a patient who has been well controlled on his previous MSI (eg, A1C <7.0 percent), the initial total daily dose of insulin administered by pump may be 10 to 20 percent less than the total daily dose of the previous regimen.Conversely, patients with inadequate glycemic control may be started with the same total daily dose as they had been using with their injection regimens.
36In general, approximately one-half of the total daily dose is administered as basal rate. For most patients, basal rates are in the range of 0.01 to units per kg per hour (ie, for a 60 kg woman approximately 0.6 to 0.9 units per hour).
37Advantages of CSII instead of MSI Slightly better glycemic control (lower A1C)The use of very-rapid-acting insulin instead of regular may result in a lower A1C, less hypoglycemia, and less weight gainMore flexibility in the timing of mealsInsulin absorption is less variable from day to day
38 Disadvantages of CSII instead of MSI CostInfection at the site of needle insertioninfusion-system failureDKA is more common
43UKPDS: Effect of Intensive Therapy on Glycemia UKPDS Group. Lancet. 1998;352:
44UKPDS 10-Year Cohort Data: Reductions With Intensive vs UKPDS 10-Year Cohort Data: Reductions With Intensive vs. Conventional TherapyUKPDS Group. Lancet. 1998;352:
45Summary of Key Findings Kumamoto 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
46Strategies 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
47Combination 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
49Meta-Analysis of Sulfonylurea/Insulin Combination Therapy Johnson JL, et al. Arch Intern Med. 1996;156:
50Comparison of Insulin Regimens Among Oral Treatment Failures Yki-Jarvinen H, et al. N Engl J Med. 1992;327:
51Need 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
52Insulin 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
54Inhaled Insulin Formulations Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.
55Continuous 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
56Conclusions 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
57Conclusions (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
59Type of insulin available Regular insulinInsulin analogues, Lispro, GlargineAlternate delivery system pump , pulmonary, intranasal , ocular, rectal , transdermalCombination with oral agentsInitiating insulin in patient on oral agents bedtime insulin
60What regimens are best for type 1? Newly diagnosed patients or latent autoimmune DM may do well receiving once or twice basal insulinPhysiological regimens or both prandial and basal insulin is required in severe insulin deficiency
61Practical strategy to start insulin in type 2 DM Continue oral agents at the same dose (eventually reduce)Add single evening dose(5 -10 IU) for thin and (10-15 IU) for obese patientsAdjust dose weekly 2-4 IU
62How dose the patient use supplement and adjustment ? A conservative dose for type 1 is additional 1 IU per 50 mg /dl above the targetFor type 2 DM 1IU per 30 mg/dl above the targetIf patients are to inject supplements less than 3 hours after previous insulin they can decrease it 50%
63Meal bolus insulin Exercise * The dose should be decrease by 30% for postprandial exercise of less than one hour, 40 % for 1-2 hours, 50 % for more than two hoursFood* Insulin requirement approximately 1 unit of insulin per 15 g carbohydrate
64ExperienceEach patient must educated for insulin and blood glucose and record dataBlood glucose and insulin logs should be reviewed weekly until goal
65Discontinuation of insulin in T2DM Reduce the dose by 10 to 15% of total doseIf the blood glucose rise, restore the initial doseIf the blood glucose dose not rise reduce 10 %- 15% every 1-2 weeksWhen daily dose reached to u/kg consider discontinuing insulin
66Benefits of combination therapy? Reduces fasting and postprandial glucoseDirectly suppresses hepatic glucose productionReduce free fatty acid levelsCounteracts dawn phenomenonMinimal education neededEasily started on an outpatient stateBetter complianceLess total exogenous insulin needed