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Insulin therapy in Type 2 Diabetes: Current and Future Directions

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Title: Insulin therapy in Type 2 Diabetes: Current and Future Directions


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Insulin therapy in Type 2 DiabetesCurrent and
Future Directions
3
When we started insulin?
  1. Type 1
  2. Sometimes Type 2

4
Pharmacologic Therapy for Type 2 Diabetes
  • Sulfonylureas (glyburide, glipizide, glimepiride)
  • Biguanides (metformin)
  • Alpha-glucosidase inhibitors (acarbose, miglitol,
    voglibose)
  • Benzoic acid analogues (repaglinide)
  • Thiazolidinediones (troglitazone, rosiglitazone,
    pioglitazone)
  • Insulin (human insulin, insulin analogues)

5
Treatment Algorithm
Nonpharmacologic therapy
Very symptomatic Severe hyperglycemia Ketosis Late
nt autoimmune diabetes Pregnancy
Monotherapy Sulfonylureas/Benzoic acid
analogue Biguanide Alpha-glucosidase
inhibitors Thiazolidinediones Insulin
Combination therapy
Insulin
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  • All 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.

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Indications 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

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  • Type 2 DM
  • Patient with persistent elevated FPG leves (200-
    300mg/dl) or ketonuria or ketonemia
  • FPG more than 300 mg/dl with polyuria, polydipsia
    and weight loss
  • Gestational diabetes
  • Uncontrolled diabetes with oral agents
  • Physician-patient option wish to receive insulin
    as initial therapy
  • Wasting state
  • Latent autoimmune diabetes in adult
  • Post MI
  • Renal failure
  • Allergy or serious reaction to oral agents

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Types of insulin
10
Types of insulin
  •  Insulin glargine
  • No real advantage with regard to A1C
  • Lower fasting blood glucose and fewer
    hypoglycemic episodes
  • Do not mix with other insulin

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GlargineA New Long-Acting Insulin Analogue
  • Modifications to human insulin chain
  • Substitution of glycine at position A21
  • Addition of two arginines at position B30
  • Unique release pattern from injection site

12
Characteristics of Insulin Glargine
  • Euglycemic clamp studies vs. NPH
  • Smooth continuous release from injection site
  • Longer duration of action
  • Continued effect at end of 24-hour clamp study
  • No differences in the absorption rate from arm,
    leg, or abdominal sites
  • No inflammatory reactions at any of the injection
    sites
  • Flat insulin profile
  • As effective in lowering FPG levels as NPH
    insulin, with significantly reduced nocturnal
    hypoglycemia

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Insulin detemir
  • Its 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

16
Very-rapid-acting insulin
  • lispro,
  • aspart
  • glulisine

Onset of action within 5 to15 Peak action at 30
to 90 Duration of action of two to four hours.
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Clinical Efficacy of Insulin Lispro
  • Worldwide clinical trials of insulin lispro in
    gt10,000 patients with type 1 or type 2 diabetes
  • Dosage 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

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Advantages of very rapid acting to regular
  • decreases the postprandial rise in blood glucose
  • reduce the frequency of hypoglycemia
  • It is more convenient because it can be injected
    immediately before meals
  • No difference in A1C
  • Need to increase in the dose of NPH when a
    patient is switched from regular insulin to a
    very-rapid-acting insulin

19
  • The 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.

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CHOICE OF INSULIN REGIMEN
  • The basic requirements are
  • Baseline dose of insulin (whether an intermediate
    or long-acting insulin or given via CSII) plus
  • Adjustable doses of pre-meal rapid-acting insulin
    (regular) or very-rapid-acting insulin analogs
    (lispro, aspart, or glulisine).

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Method of Insulin Preparation
  • Conventional insulin therapy
  • Intensive insulin therapy
  • MSI
  • CSII

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Getting started
  • Start 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 time
  • The 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.

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Conventional insulin therapy
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Methods of MSI
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Major drawback to intensive therapy
  • Cost (three times )
  • Weight gain
  • Risk of hypoglycemia (three times)

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When to start intensive therapy
  • Intensive therapy should be started as early as
    possible following the diagnosis of type 1
    diabetes.

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  • Intensive insulin therapy

Residual beta cell function
lower risk of hypoglycemia
31
MANAGEMENT ISSUES
  • Consistency
  • The content and timing of meals,
  • The site of insulin injections,
  • The timing and frequency of exercise.
  • SMBG
  • Four to seven times daily

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Insulin Pump
  • CSII uses portable infusion pump connected to an
    indwelling subcutaneous catheter to deliver
    short-acting insulin

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MSI or CSII
  • Same efficacy,
  • Same frequency of hypoglycemic events,
  • Same impact on quality of life for most patients

35
MSI CSII
  • For a patient who has been well controlled on his
    previous MSI (eg, A1C lt7.0 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.

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  • In 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 0.015 units per kg per hour (ie, for a
    60 kg woman approximately 0.6 to 0.9 units per
    hour).

37
Advantages 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 gain
  • More flexibility in the timing of meals
  • Insulin absorption is less variable from day to
    day

38
 Disadvantages of CSII instead of MSI
  • Cost
  • Infection at the site of needle insertion
  • infusion-system failure
  • DKA is more common

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Insulin Pump
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Insulin therapy in Type 2 DiabetesCurrent and
Future Directions
41
Pharmacologic Therapy for Type 2 Diabetes
  • Sulfonylureas (glyburide, glipizide, glimepiride)
  • Biguanides (metformin)
  • Alpha-glucosidase inhibitors (acarbose, miglitol,
    voglibose)
  • Benzoic acid analogues (repaglinide)
  • Thiazolidinediones (troglitazone, rosiglitazone,
    pioglitazone)
  • Insulin (human insulin, insulin analogues)

42
Treatment Algorithm
Nonpharmacologic therapy
Very symptomatic Severe hyperglycemia Ketosis Late
nt autoimmune diabetes Pregnancy
Monotherapy Sulfonylureas/Benzoic acid
analogue Biguanide Alpha-glucosidase
inhibitors Thiazolidinediones Insulin
Combination therapy
Insulin
43
UKPDS Effect of Intensive Therapy on Glycemia
UKPDS Group. Lancet. 1998352837-853.
44
UKPDS 10-Year Cohort Data Reductions With
Intensive vs. Conventional Therapy
UKPDS Group. Lancet. 1998352837-853.
45
Summary of Key Findings
  • Kumamoto trial
  • Intensive insulin treatment reduced microvascular
    complications
  • Established glycemic threshold to prevent onset
    and progression of complications
  • UKPDS
  • Diet therapy alone inadequate in two thirds of
    patients
  • Pharmacologic therapy plus nutrition/exercise
    necessary
  • Weigh benefitrisk ratio
  • No threshold for HbA1c reduction in reducing
    complications
  • Insulin does not increase macrovascular disease

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Strategies for Insulin Therapy in Elderly Patients
  • Insulin therapy often considered a last resort in
    the elderly
  • Therapeutic goals
  • Relieve symptoms
  • Prevent hypoglycemia
  • Prevent acute complications of hyperglycemia
  • Ways to facilitate insulin treatment
  • Simple dose schedules
  • Premixed preparations
  • Improved, more convenient delivery systems

47
Combination Therapy Oral Agents Plus Insulin
  • Rationale
  • Combination of two agents with different
    mechanisms of action
  • More convenient and may be safer
  • Sulfonylurea Insulin
  • BIDS therapy bedtime insulin/daytime
    sulfonylurea
  • Useful in patients early in course of disease
  • Metformin Insulin
  • Improves insulin sensitivity
  • Alpha glucosidase inhibitor (acarbose) Insulin
  • Decreases postprandial glycemia
  • Thiazolidinediones Insulin
  • Improves insulin resistance, improves insulin
    action in peripheral tissues
  • Reduces insulin requirement

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Meta-Analysis of Sulfonylurea/InsulinCombination
Therapy
Johnson JL, et al. Arch Intern Med.
1996156259-264.
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Comparison of Insulin RegimensAmong Oral
Treatment Failures
Yki-Jarvinen H, et al. N Engl J Med.
19923271426-1433.
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Need for Novel Delivery Systems of Insulin
  • Disadvantages of conventional subcutaneous
    injection
  • Discomfort
  • Inconvenience
  • Systemic delivery
  • Inconsistent pharmacokinetics
  • Irreversible after injection
  • Insulin pumps too complex, limited experience
    and utility with type 2
  • Insulin pen beneficial but underutilized
  • Systems in clinical testing
  • Inhaled formulation
  • Jet-injected systems

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Insulin Pen
  • Benefits
  • More accurate dosing mechanisms
  • Faster and easier than conventional syringes
  • Improved patient attitude and compliance
  • Advantages of newer insulin pens
  • LCD display to show dosage setting
  • Dosage settings change quickly and easily
  • Safety button automatically resets after drug
    delivery

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Insulin Pen
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Inhaled Insulin Formulations
Gelfand RA, et al. Presented at ADA 58th Annual
Meeting. 1998Abstract 0235.
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Continuous Glucose Sensors
  • When available, may provide only mechanical means
    of achieving normal glucose homeostasis
  • Will direct insulin delivery automatically on
    demand (closed loop)
  • One technology uses reverse iontophoresis to
    noninvasively extract and measure glucose levels
  • Technical challenge to develop

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Conclusions
  • Type 2 diabetes gradual deterioration of
    glycemic control
  • Significant morbidity and mortality tight
    glycemic control reduces risk of complications
  • Earlier institution of insulin may help attain
    initial glycemic control
  • Objectives of insulin therapy
  • Achieve normal fasting glucose levels
  • Achieve normal postprandial glucose levels
  • Minimize hypoglycemia
  • Intensive insulin therapy should
  • Provide good glycemic control
  • Produce little hypoglycemia
  • Improve lipid profile
  • Reduce risks and costs of treating complications

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Conclusions (contd)
  • New delivery systems
  • Reduce limitations of conventional insulin
    syringes
  • Improve patient compliance and disease management
  • New long-acting insulin analogues (eg, insulin
    glargine)
  • Produce flat insulin profile with no peaks
  • Allow once-daily administration
  • Significantly reduce nocturnal hypoglycemia

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Type of insulin available
  • Regular insulin
  • Insulin analogues, Lispro, Glargine
  • Alternate delivery system pump , pulmonary,
    intranasal , ocular, rectal , transdermal
  • Combination with oral agents
  • Initiating insulin in patient on oral agents
    bedtime insulin

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What regimens are best for type 1?
  • Newly diagnosed patients or latent autoimmune DM
    may do well receiving once or twice basal insulin
  • Physiological regimens or both prandial and basal
    insulin is required in severe insulin deficiency

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Practical 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 patients
  • Adjust dose weekly 2-4 IU

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How dose the patient use supplement and
adjustment ?
  • A conservative dose for type 1 is additional 1 IU
    per 50 mg /dl above the target
  • For type 2 DM 1IU per 30 mg/dl above the target
  • If patients are to inject supplements less than 3
    hours after previous insulin they can decrease it
    50

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Meal 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 hours
  • Food
  • Insulin requirement approximately 1 unit of
    insulin per 15 g carbohydrate

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Experience
  • Each patient must educated for insulin and blood
    glucose and record data
  • Blood glucose and insulin logs should be reviewed
    weekly until goal

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Discontinuation of insulin in T2DM
  • Reduce the dose by 10 to 15 of total dose
  • If the blood glucose rise, restore the initial
    dose
  • If the blood glucose dose not rise reduce 10 -
    15 every 1-2 weeks
  • When daily dose reached to 0.2- 0.4 u/kg consider
    discontinuing insulin

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Benefits of combination therapy?
  • Reduces fasting and postprandial glucose
  • Directly suppresses hepatic glucose production
  • Reduce free fatty acid levels
  • Counteracts dawn phenomenon
  • Minimal education needed
  • Easily started on an outpatient state
  • Better compliance
  • Less total exogenous insulin needed

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