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Design and Management of Insulin Therapy: Integrating the New Treatment Tools

  • Authors: Ramachandiran Cooppan, MD
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Target Audience and Goal Statement

The target audience of this Internet enduring material is primary care clinicians (MDs, DOs, NPs, PAs) and specialists (endocrinologists, diabetologists).

This activity discusses normal insulin physiology, and outlines the pathophysiologic changes in insulin secretory patterns and action that are seen with both type 1 and type 2 diabetes. It presents the currently available insulins for replacement therapy, covers strategies and techniques for patient assessment from a functional and pathophysiologic perspective, and describes options for designing an insulin replacement program. It also reviews how current approaches to insulin therapy fit into the overall spectrum of therapeutic options for people with type 2 diabetes.

Participants will be provided with clinically relevant, evidence-based information. At the completion of the activity, the participant should be able to:

  1. Describe the natural history of insulin secretory decline in people with type 1 and type 2 diabetes;
  2. Assess the individualized pathophysiologic state of insulin secretory decline in people with type 1 and type 2 diabetes;
  3. Design insulin treatment programs to restore normal glucose patterns in pre- and postprandial periods based on the pathophysiologic assessment of type 1 and type 2 diabetes;
  4. Initiate and manage insulin treatment programs, including inhaled-insulin regimens.


As part of its accreditation with the Accreditation Council for Continuing Medical Education, Joslin Diabetes Center, Boston, must disclose to the audience of a Joslin continuing medical education activity the existence of any relevant financial relationships between Joslin and/or its planning committee members, speakers, and their spouses/partners and commercial entities. Joslin and its planning committee members and speakers must disclose any relationships they and their spouses/partners have or have had in the prior 12 months with proprietary entities producing healthcare goods or services with the exception of non-profit or government organizations and non-healthcare related companies, which are exempt.

Financial relationships are those relationships in which the individual benefits by receiving a salary, royalty, intellectual property rights, consulting fees, honoraria, ownership interests (e.g., stocks, stock options or other ownership interest, excluding diversified mutual funds) or other financial benefit in any amount. Financial benefits are usually associated with roles such as employment, management position, independent contractor (including contracted research), consulting, speaking and teaching, membership on advisory committees or review panels, board membership, and other activities from which remuneration is received, or expected.

If a faculty or planning committee member has no information to disclose, this information will also be provided. If a faculty or planning committee member refuses to disclose, he/she will not be able to participate in the planning, management, presentation, or evaluation of any Joslin Diabetes Center CME activity. In addition, faculty have been asked to disclose when a product or device is not labeled for the use under discussion. The opinions and comments expressed in this program are those of the speakers and should not be considered the opinions or comments of the Joslin Diabetes Center.


  • Ramachandiran Cooppan, MD

    Assistant Clinical Professor of Medicine, Harvard Medical School; Consultant, Professional Education, Joslin Diabetes Center, Boston, MA


    Disclosure: Speakers Bureau: Amylin Pharmaceuticals, Inc., Bristol-Myers Squibb Company, GlaxoSmithKline, Eli Lilly and Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc, sanofi-aventis U.S. LLC, Takeda Pharmaceuticals North America, Inc.

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    The Joslin Diabetes Center designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Design and Management of Insulin Therapy: Integrating the New Treatment Tools

Authors: Ramachandiran Cooppan, MDFaculty and Disclosures


Use of Insulin in Type 1 and Type 2 Diabetes

Dr. Weissman has given us a wonderful background in terms of the pathophysiology of diabetes and the tools to treat it. My task will be to walk through some of the mental processes we go through when we initiate insulin therapy, how we make those decisions, and how we try to maintain an effective insulin treatment program.

  • The discovery of insulin in 1921 was a quantum leap for patients with diabetes. Without insulin, this young girl would have died in a matter of days or weeks. Insulin is life-saving in type 1 diabetes.

  • Slide 1. Before and After

    Slide 1.

    Before and After

    (Enlarge Slide)
  • With the use of insulin, we have made tremendous strides. This is a vial of the earliest extract of insulin from the University of Toronto, Ontario, Canada. There has been great progress made in terms of purification, from an animal source-based insulin to the current era of "designer insulins," as well as changes in the routes of administration.

  • Slide 2. Early Extract of Insulin

    Slide 2.

    Early Extract of Insulin

    (Enlarge Slide)
  • For a patient with type 1 diabetes more than 35 years ago, we used a more conventional approach, which was a split mix; it was either lente or neutral protamine Hagedorn (NPH) with regular insulin, twice daily. We varied that and did urine testing. Today, if we see a patient with type 1 diabetes, we almost immediately use basal/bolus therapy. The physiologic insulin replacement is the closest we have to mimicking normal physiology. And unless that patient is going through a remission, invariably this is where he or she will end up.

    What varies today is the delivery route. For some patients, it may be a subcutaneous insulin infusion pump, and for others it will be basal/bolus insulin injections. In addition, we have a new tool; inhaled insulin available as a prandial insulin option.

  • Slide 3. Possible Evolution Pathways of an Insulin Treatment Program for Type 1 DM

    Slide 3.

    Possible Evolution Pathways of an Insulin Treatment Program for Type 1 DM

    (Enlarge Slide)
  • The type 2 diabetes paradigm is still evolving. In general, the pathophysiology of type 2 diabetes results in a defect in insulin secretion as well as in insulin action. The natural history has been a progressive decline in beta-cell function, leading to greater and greater need for insulin replacement therapy as a supplement.

    In some instances, a patient with type 2 diabetes will start with insulin. This may be an individual who is symptomatic or losing weight. Or, some type 2 diabetes patients may present with ketoacidosis, recover, and be able to be controlled once again on oral therapy. But the traditional scenario is that our patients have gone through oral medicines and are no longer adequately controlling the blood glucose levels to goal. In this instance, we initiate therapies with insulin.

    The traditional model has been evolving to where we would introduce a basal type of insulin based on an understanding of the pathophysiology that as insulin secretion decreases, hepatic glucose production rises, and therefore fasting glucoses rise. So using a nighttime dose of insulin would suppress the liver's output of glucose and lower the fasting level. In general, this is a very effective therapy and is probably better than using 3 drugs; triple oral agents, at best, may lower A1C by 1%. In addition, any woman who is pregnant and has diabetes will be on insulin.

    Another question that keeps coming up, which I think is becoming even more of an issue, is the role of postprandial hyperglycemia, not only in terms of microvascular disease, but also the potential role either the hyperglycemia or the posthyperglycemic metabolic state may contribute to cardiovascular risk. Another question is whether there is a place in our strategies for using prandial insulins earlier. In order to get A1C to less than 7%, you have to lower both fasting and postprandial glucose. But there are instances when patients may have, predominantly, a single peak in a postprandial glucose that you target. But you are going to base that decision on the glucose profile from glucose monitoring, and then adapt the tools that will work best.

  • Slide 4. Current Paradigm for Insulin Use in People With Type 2 Diabetes

    Slide 4.

    Current Paradigm for Insulin Use in People With Type 2 Diabetes

    (Enlarge Slide)
  • Reviewing the therapies, it does not matter whether patients take insulin or oral medicines; you cannot escape the fact that diabetes is a disease that has to do with food, eating, and insulin production. In general, the traditional model was to start with diet and exercise, then wait to use an oral medicine.

    The most current guidelines suggest that we start with an oral medicine and diet and exercise together, and the drug that the American Diabetes Association (ADA) has recommended in that scenario is metformin. Then if one drug does not work, we add another, and in some instances we will add even a third one. This has been the paradigm, and when that did not work and you notice that now we are up to over 10 years from the diagnosis, then insulin would be added, if it was added at all. The new ADA guidelines recommend adding insulin much earlier in the treatment to avoid this delay.

    That scenario has changed because therapies in the toolbox are increasing. Now we have the glucagon-like peptide-1 (GLP-1) analogs that you heard mentioned, wonderful therapies that have taken away the issue of "I do not like shots," and the dipeptidyl peptidase-IV (DPP-IV) inhibitors, a clear example of understanding pathophysiology and then devising a therapeutic strategy that works.

    For those patients on insulin for whom you wanted to control postprandial hyperglycemia and you have tried with regular insulin or a rapid-acting insulin analog with nutritional manipulations, pramlintide, which is an analog of amylin, is a very good postprandial glucose-controlling agent, suppressing glucagon levels and improving postprandial glucose. It can only be used with insulin therapy. The latest therapy is inhaled insulin, and we are trying to decide where it fits in, it is a prandial insulin; it is not a basal insulin and it is not to be used that way.

  • Slide 5. Type 2 Diabetes: Evolving Treatment Paradigm

    Slide 5.

    Type 2 Diabetes: Evolving Treatment Paradigm

    (Enlarge Slide)

Insulin Therapy: Obstacles, Barriers, Challenges

  • One thing is clear: we seem to have a problem, and it is clinical inertia. We have this disease that is progressing, yet we seem to be standing still in making our decisions, and it is not because of a lack of tools.

    This study came out of the Kaiser Permanente group in California. They looked at how many patients moved to the next level of treatment when A1C was over 8%. Of patients taking sulfonylureas, only 35% went to the next stage, which would probably be a combination of 2 pills. If patients were on metformin, 44% had another treatment. But when patients were on 2 drugs, only 18% went to the next step, because the next step is insulin. In general, patients spent 5 years with an A1C over 8% before a decision was made. That is unacceptable, certainly from the patient's point of view. We need to be much more proactive as we understand the pathophysiology of diabetes.

  • Slide 6. Clinical Inertia: "Failure to advance therapy when required"

    Slide 6.

    Clinical Inertia: "Failure to advance therapy when required"

    (Enlarge Slide)
  • There are barriers to insulin use. There are patient issues; we call this "psychological insulin resistance." However, the needles today are very fine; self-glucose monitoring is far more painful. But patients have this idea that shots will scar them, and they are going to be painful.

    Practitioners are very busy. When we use insulin therapy, we start at one point and we may end up at a very complex place, using intensive therapy, which is time-consuming, requires staff, and requires a lot of input. When you use multiple daily injections (MDI) or intensive therapy, someone has to be on call to treat these patients. Consequently, available resources sometimes determine the steps we take.

    We also know that patients are very savvy. They know that insulin causes you to gain weight. Why do you think the use of GLP-1 analogs is going up so fast? They control blood glucose, and you lose weight at the same time.

    Hypoglycemia is very real. If you have experienced hypoglycemia, all you can think of is food. It is not a nice feeling.

    And finally, I think we recognize that for optimal control of diabetes we should be prepared to use multiple injections. One of the things we never do is to promise our patients that there will only be 1 shot a day. It is going to be as many shots as it takes.

  • Slide 7. Barriers to Insulin Use

    Slide 7.

    Barriers to Insulin Use

    (Enlarge Slide)
  • This study was published in 1999. Zambanini and colleagues assessed type 1 and type 2 patients to determine some of the reasons for this resistance. People are troubled by the idea that they may take more than 1 shot per day. They do not like the insulin injection; there is anxiety about sticking themselves. Even when they took the patients who were very anxious, whom we would think do not want to take insulin at all, their major concern appeared to be whether they would end up with more than 1 daily injection. But if the "return" for using that treatment is good, patients overcome that barrier.

  • Slide 8. Barriers to Insulin Use: Resistance Among Patients With Type 1 and Type 2 Diabetes

    Slide 8.

    Barriers to Insulin Use: Resistance Among Patients With Type 1 and Type 2 Diabetes

    (Enlarge Slide)
  • Providers have to overcome these obstacles. We have to set very appropriate goals for our patients, individualizing the approach. Education of the patient and others involved in their care is very, very important. The advent of premixed insulins has been very helpful for those select patients who require good control, but not necessarily getting A1Cs to 7% or less.

    We will discuss inhaled insulin. Certainly, at the back of our mind, our strategy is always to try and mimic normal physiology. And there have been great advances in terms of the insulin syringes, from the days of glass syringes boiled to maintain sterility. Today insulin is available in pen devices. It costs a little more, but they are portable, and often these pens have easy-to-see dials. People who may have visual issues can hear the clicks.

  • Slide 9. Insulin Treatment of Type 2 Diabetes: Overcoming Patient Obstacles

    Slide 9.

    Insulin Treatment of Type 2 Diabetes: Overcoming Patient Obstacles

    (Enlarge Slide)

Considering the Next Steps in Insulin Therapy

  • When I was practicing at the Joslin Diabetes Center, I could send the patient to the nurse practitioner, dietician, nurse educator, exercise physiologist, or psychologist; you name it, we had it. But what do you do in your own office practice?

    Diabetes is a great example of a team approach, and the people may be in your office, or they may be in the community. As the provider, you need to identify those resources. If you have someone in your office who is taking on a support role and will be liaising with patients, they need to be knowledgeable about the differences between type 1 and type 2 diabetes, why we choose different therapies, and what factors raise and lower glucose. They need to look at glucose patterns. We are asking patients to test their blood glucose, and the worst thing to do is not to review them when they bring them to us; otherwise it is a useless exercise. So knowing how to interpret glucose patterns is very important. Support staff also should be educated in the role of different types of food and their effect, exercise, etc., and how to respond to emergencies. This type of education is very important.

  • Slide 10.  Insulin Treatment in the Primary Care Setting: Basic Knowledge for Office Support Staff

    Slide 10.

    Insulin Treatment in the Primary Care Setting: Basic Knowledge for Office Support Staff

    (Enlarge Slide)
  • Furthermore, in many of these situations you may rely on your nurse to teach meter use, and that would involve determining the patient's ability to participate in their care. Diabetes is a self-management disease, and you need to assess the patient's self-care ability, and then involve other appropriate caregivers if necessary.

    Knowing how to inject insulin is very important. Every patient has to learn how to inject insulin if they are taking insulin, even if it is inhaled, because a device may malfunction and may require them to use injection instead. It is similar to patients on an intermediate-acting insulin once a day; we also provide them with a vial of rapid-acting insulin that may be necessary for emergencies. With inhaled insulin, there will be a new challenge for us regarding lung function, which is a critical part of using this current tool.

    If you decide that the patient needs to go to the next step, what are some of the factors to consider in making these choices? You want to balance the treatment goals with the medical needs of patients, and have a very holistic approach to other conditions, other comorbid diseases. Safety is always of primary importance. We would also like as flexible a program as we can devise, and we want a good assessment of the patient. We ask how they will interact with us in this program: Can they make the judgments that will be required for some of these sophisticated tools?

    Psychosocial and cultural issues are very important. We have to take them in context, because they influence the kind of healthcare beliefs patients grow up with and their expectations. Physical and mental limitations may also come into play.

  • Slide 11. Insulin Treatment in the Primary Care Setting: Office Support Staff Systems and Functions

    Slide 11.

    Insulin Treatment in the Primary Care Setting: Office Support Staff Systems and Functions

    (Enlarge Slide)
  • In terms of determining what therapeutic tool you are going to use, one of the most important assessments is glycosylated hemoglobin (A1C). If you see a patient who has had 5 or more years of type 2 diabetes, is on two drugs, and their A1C is 10% or 12%, it is not coming down to 7% with another drug; if A1C is 8%, you can probably get it down to 7%, with a third drug. So the level of A1C is very important, especially with longer-duration diabetes. Early in the disease, when it is newly diagnosed, the higher the A1C, the bigger the decrease with initial treatment but this changes with time as beta-cell insulin secretion decreases.

    Postprandial hyperglycemia has to be monitored, and is a target for control. The current level set by the ADA is less than 180 mg/dL but the American Association of Clinical Endocrinologists (AACE) sets a specified 2-hour value of less than 140 mg/dL

  • Slide 12. Specific Considerations in Determining the Next Therapeutic Step

    Slide 12.

    Specific Considerations in Determining the Next Therapeutic Step

    (Enlarge Slide)
  • There are a variety of insulin pens available, and these are wonderful tools to use. Some of them even come with little meters attached. So you carry this with you, test your blood glucose, decide what you are going to eat, put in the fast-acting insulin, come home, and take your basal insulin. There is a great deal of portability as well as flexibility available to our patients today.

  • Slide 13. Examples of Insulin Pen Delivery Devices

    Slide 13.

    Examples of Insulin Pen Delivery Devices

    (Enlarge Slide)

Consideration in Use of Inhaled Insulin

  • What about inhaled insulin? Ever since the initial discovery of insulin and its purification, patients have been trying to avoid injections. Insulin was initially used 4 times a day. Then they developed protamine zinc insulin, which was given once a day. It took the Diabetes Control and Complications Trial (DCCT) to bring us full circle, back to 4 shots a day, because this offered the best control.

    There is also a constant quest to find alternate routes of administration. Investigators looked at drops in the eyes, rectal administration, nasal insulin, dermal patches, and oral insulin. The one that became the primary target was inhalation of insulin, because there was precedent for this approach; patients inhale many different drugs (bronchodilators, steroids).

    The lung is a very vascular bed, and when appropriate particle-size medication gets into the lung, it is very rapidly absorbed into the circulation. So it was natural that people would look at this route of administration for insulin.

    The only inhaled insulin that is approved by the US Food and Drug Administration is Exubera (insulin human [rDNA origin]) Inhalation Powder. [Editor's note: this statement is true as of October 3, 2007]. Being the only approved inhaled insulin, more data have been collected on this particular medication than on any others at this time.

    In preparation for the evolution of this class, it is important to distinguish here between data that are specific to the approved product, Exubera, and data that are general to the class. As other products become approved, these distinctions could be extremely important. Therefore, to clarify for you and because the generic terminology is not clear at this point in time, I will use the term "Exubera" when data are specific to this inhaled insulin product. "Inhaled insulin" is used when referring to the general class of insulin via the inhalation route.

    Exubera (human insulin [rDNA origin]) inhalation powder uses particles that are between 1 and 5 microns in diameter, the optimal size for inhalation. Other forms in development include AERx (NovoNordisk), AIR (Lilly), Spiro (Dura), Technosphere Insulin (MannKind), and Aerodose (Aerogen). Some are not powder but aerosol. Their excipients and medication delivery systems also differ.

    Exubera (human insulin [rDNA origin]) inhalation powder is packaged in a blister pack. For the first time, insulin, which we usually talk about in units, is being presented to us in milligrams. You have a 1-mg pack, which has 3 units of insulin, and a 3-mg pack, which has 8 units. The blister pack is placed in an inhalation device.

  • Slide 14. Inhaled Insulin: A Novel Delivery System

    Slide 14.

    Inhaled Insulin: A Novel Delivery System

    (Enlarge Slide)
  • The blister pack goes in the chamber, and there is a handle that the patient squeezes, which increases compressed air in the chamber, the insulin is aerosolized, and then the patient puts the inhaler in their mouth and inhales for about 5 seconds, and then releases the handle. If using multiple doses, you have to keep repeating that process. Other devices exist. Some are smaller, and some have electronic chips that activate at the correct time; if the patient tries to hold their breath, it will not work.

  • Slide 15. Insulin Dry Aerosol Inhaler

    Slide 15.

    Insulin Dry Aerosol Inhaler

    (Enlarge Slide)
  • The indications for Exubera are similar to any prandial insulin. It is for the treatment of adults with diabetes when other methods have not controlled their hyperglycemia. In the type 2 diabetes population, you can combine this with oral medicines, or you can us must be used e it as monotherapy. In a type 1 diabetes population, it replaces the prandial injection, but must be used together with basal insulin. It is not approved for use in pregnancy or pediatric patients at the present time. A big factor is that it is contraindicated in patients with unstable or poorly controlled lung disease, and there are some interesting issues around the absorption of insulin in these circumstances.

    When they studied the pharmacokinetics of Exubera, age, gender, race, and body mass index do not seem to have an effect. The only difference is that the heavier patients may require more insulin if they are insulin resistant. Very interestingly, smoking increases the absorption rate, although cigarette smoking is an absolute contraindication. The bioavailability of Exubera is much higher with chronic lung disease, but lower with asthma. We do not have data to know why, except to say that this is being studied progressively as more patients use the product. And it is comparable in peak action to analog rapid-acting insulin such as lispro. However the duration of action is more like regular insulin.

  • Slide 16. Inhaled Insulin: Indications and Contraindications

    Slide 16.

    Inhaled Insulin: Indications and Contraindications

    (Enlarge Slide)
  • How do you dose Exubera inhaled insulin? You can use a formula: you administer .05 mg/kg of body weight, which is your premeal dose. And you have to round up to the nearest whole number.

    As I mentioned, blisters are produced as 1- and 3-mg packets. So you do not want to allow a patient who is taking a 3-mg blister based upon your calculation to take three 1-mg blisters because they will be getting 9, not 8, units of insulin. In general, that may not be important, but for type 1 diabetes patients, 1 unit can be very important; so you have to be careful.

  • Slide 17. Initial Dosing: Inhaled Insulin

    Slide 17.

    Initial Dosing: Inhaled Insulin

    (Enlarge Slide)
  • Another approach, if you know the weight of your patient, is in the Exubera package insert. [Note that the recommended initial dose per meal that is indicated in this table is 1 mg below what is noted in the package insert for patients weighing 40-59.9 kg and 100-119.9 kg. This change is effective July 2007.] They recommend an initial dose of inhaled insulin per meal. So if the patient weighs 80 kg, they will require 4 mg for that meal, which is about 11 units. How do you get 11 units? You take 1 of the 3-mg blisters and 1 of the 1-mg blisters. And patients would have to administer each of these blisters separately. This is the current approach.

  • Slide 18. Guidelines for Initial Pre-meal Inhaled Insulin Dosing Based on Patient Body Weight

    Slide 18.

    Guidelines for Initial Pre-meal Inhaled Insulin Dosing Based on Patient Body Weight

    (Enlarge Slide)
  • If one has started an insulin program, glucose monitoring becomes very important, and we have targets that need to be reached. If using inhaled insulin, it is titrated like any other prandial insulin. All of the traditional factors, the glucose concentration, the meal size, the composition, the carbohydrate content, the glycemic index, the time of the day, exercise, etc., are considered. You will make the same assessments and then adjust the dosage.

  • Slide 19. Considerations for Dose Titration

    Slide 19.

    Considerations for Dose Titration

    (Enlarge Slide)

Pulmonary Assessment During Inhaled Insulin Therapy

  • There are some very strict guidelines for pulmonary assessment. Every patient to be put on Exubera must have spirometry done. Who is going to do the test? What do you do in your office? Contact the local hospital to have the test done or if you are going to do it in your office, you need to make sure that you are proficient with spirometry and what the standardizations are, the interpretation of which cannot vary from patient to patient. Diffusing capacity of the lung for carbon monoxide (DLCO) is an optional assessment that you generally will not need to do.

    We measure the forced expiratory volume in 1 second (FEV1). If the FEV1 is less than 70% of predicted, you cannot use Exubera. The guidelines for use also recommend a 6-month follow-up test, and yearly or more frequently if indicated. For instance, if a patient's cough has not disappeared, you might want to repeat it. If there is a decline in pulmonary function while the patient is on the insulin and if FEV1 declines more than 20% (or more than 500 mL in volume), then repeat the test. If it is still the same, stop the insulin. If a patient is very symptomatic in other ways, with chest discomfort and just not feeling right, you may have to discontinue inhaled insulin under those circumstances.

    Contraindications include hypersensitivity to inhaled insulin itself. Smokers or patients who have stopped smoking within 6 months should not be on inhaled insulin. If the patient resumes smoking, you have to discontinue the inhaled insulin immediately.

    In terms of unstable and poorly controlled lung disease being a contraindication, the reason for this is there may be variation in the absorption of the insulin. Although we do not know exactly what is meant by unstable or poorly controlled lung disease (for example, patients with chronic obstructive pulmonary disease, asthma, etc.), it would be prudent at the present time to not consider those patients as candidates for inhaled insulin.

  • Slide 20.  Recommendations for Pulmonary Assessment During Inhaled Insulin Therapy

    Slide 20.

    Recommendations for Pulmonary Assessment During Inhaled Insulin Therapy

    (Enlarge Slide)
  • What if patients develop an upper respiratory tract infection, mild cold, or a little bit of bronchitis? You can continue the insulin but monitor glucose. What if they have pneumonia? Chances are you should stop it. And if they are using bronchodilators, they should be used first and the inhaled insulin should be given secondarily.

  • Slide 21. Recommendations for Pulmonary Assessment During Inhaled Insulin Therapy

    Slide 21.

    Recommendations for Pulmonary Assessment During Inhaled Insulin Therapy

    (Enlarge Slide)

Designing an Insulin Treatment Program: Basal Insulin

  • We have the option of adding a third oral agent, whether it is a sulfonylurea, a DPP-IV inhibitor, or exenatide. We are going to focus on how we move through this cascade. When do we use basal, when do we use premix, and how do we achieve basal/bolus coverage?

  • Slide 22. Revisiting the Options for Next Treatments Treatment Inadequacy With Two Medications

    Slide 22.

    Revisiting the Options for Next Treatments: Treatment Inadequacy With Two Medications

    (Enlarge Slide)
  • When you see a patient with diabetes, you have to decide the kind of program to design for this individual. Young business executives who are on the go want flexibility in terms of the shots, their travel, etc. That means choosing a program that is most flexible.

    On the other hand, the choice may be to minimize the fluctuations and the variability of insulin absorption. There are patients who can be initiated on this type of program, but cannot stay there if the situation changes. You can start with one injection, but if things change, be prepared to add on to that. Where you start determines where you go.

  • Slide 23. Considerations in Insulin Treatment Program Design

    Slide 23.

    Considerations in Insulin Treatment Program Design

    (Enlarge Slide)
  • What are the possible pathways for the evolution of an insulin treatment program for type 2 diabetes patients? One is PM insulin basal coverage (giving some insulin at night). If that does not work and postprandial glucoses go up early in the day, we would move to the split-mix approach. Today, much as in type 1 diabetes, we would offer preprandial insulin to patients who are developing postprandial hyperglycemia. That does not necessarily mean three injections or three inhalations of insulin per day for a patient with type 2 diabetes. Glycemic excursions will determine at what point you initiate preprandial insulin. Some patients may need it once; some may need it twice.

    Prandial treatment currently has been using rapid-acting insulins; glulisine, lispro, and aspart. Today, inhaled insulin comes in that cascade and will be part of treatment either as an add-on or part of a basal/bolus treatment.

  • Slide 24. Possible Evolution Pathways of an Insulin Treatment Program for Type 2 DM

    Slide 24.

    Possible Evolution Pathways of an Insulin Treatment Program for Type 2 DM

    (Enlarge Slide)
  • Assume you have a patient on two drugs. You want to start insulin, and you have chosen basal insulin because of fasting hyperglycemia. The first principal: this is add-on therapy. The oral agents stay at their current doses; no adjustments are made. You add a single dose of an insulin. This could be a long-acting basal insulin (detemir, glargine) or NPH, an intermediate-acting insulin analog, at bedtime. Insulin glargine and detemir can be used at other times but the same time daily. If the patient has postmeal hyperglycemia after dinner, perhaps a 70/30 or analog mix may be used.

    The physician then follows an adjustment algorithm. You need to make these adjustments weekly to get your patient to target, remembering that in a type 2 diabetes patient, you may end up with 40 to 50 units of a single type of insulin in order to control hyperglycemia in the fasting state. In selected patients, you can have them monitor and make adjustments every 2 or 3 days, which expedites the process. The target is to reduce fasting glucose to less than 100 mg/dL, if it can be done safely.

  • Slide 25. Option: Using Long-acting Basal Insulin at Bedtime: Initiation and Titration

    Slide 25.

    Option: Using Long-acting Basal Insulin at Bedtime: Initiation and Titration

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  • Studies have been conducted to look at basal insulin vs intermediate-acting insulin. This is a treat-to-target study, where glargine is compared with NPH in a group of patients not controlled on oral medicines. Both insulins lowered A1C from 8.6% to 7.1% in about 3 to 4 months, a very nice drop, and they required roughly equivalent doses. The difference in the study was that with glargine, there was a little less nocturnal hypoglycemia than with NPH. So for a purely fasting target, this type of an approach is a very good one.

    But in this treat-to-target study, 43% of the patients were not at an A1C goal of less than 7%. So the question is: where is the escape occurring? If the fasting glucose is looking good and A1C is not coming down, where is the next problem? As A1C comes down closer toward normal, there is a greater contribution to glycemia from postprandial glucose.

  • Slide 26. Adding Basal Insulin to Patients Treated With Antidiabetes Medications Reduces A1C Further

    Slide 26.

    Adding Basal Insulin to Patients Treated With Antidiabetes Medications Reduces A1C Further

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  • The next step would be to continue with the oral medications and, at this stage, look at glucose patterns. The patient is on basal insulin, and you want to assess the degree of pre- and postprandial hyperglycemia. You want to know whether they are getting hypoglycemic in the middle of the night, whether they are very insulin resistant and require large doses of insulin, because that will affect your decision as to what you do with the oral medicines. If you decide to add a prandial insulin, the secretagogue would be reduced or removed from the treatment program. However, if this patient is very insulin resistant, then a thiazolidinedione or metformin would remain part of the therapy for its insulin-sensitizing effects. These adjustments are being made while you are gathering the data.

  • Slide 27. Insulin Added to Antidiabetes Therapies for Patients With Type 2 Diabetes: Adjusting Medic

    Slide 27.

    Insulin Added to Antidiabetes Therapies for Patients With Type 2 Diabetes: Adjusting Medications

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Designing an Insulin Treatment Program: Split-Mix Insulin Therapy

  • If the patient has developed significant postprandial hyperglycemia, the old approach was to go to a conventional split mix. In other words, we would use an intermediate-acting insulin with some fast-acting insulin, and give that twice a day. That was the way we treated diabetes for decades, but it is not a very physiologic approach. There is a greater likelihood that NPH will peak after midnight and give you nighttime lows, and patients do not always wake up with that. The newer sources of human insulin, even the intermediate-acting insulins, are not as long lasting. So a human NPH that is made from recombinant DNA technology does not last as long as the animal-source NPH had lasted, and you can get hyperglycemia with the waning NPH action.

  • Slide 28. Option: Conventional Split-Mix Insulin Therapy

    Slide 28.

    Option: Conventional "Split-Mix" Insulin Therapy

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  • The old way of doing things was to use split mix, regular/NPH mixture, one third/two thirds, divided twice a day. In some cases, if the fasting glucose was high, the NPH was moved from suppertime to bedtime.

    There was a 3-injection program that was used a lot: a mixture in the morning, fast-acting insulin before the evening meal, and NPH at bedtime. This was aided when the very-rapid-acting insulins came on the market, because they work more physiologically.

  • Slide 29. Multiple Injection Program: NPH and Pre-Breakfast and Supper Short- or Rapid-Acting Insuli

    Slide 29.

    Multiple Injection Program: NPH and Pre-Breakfast and Supper Short- or Rapid-Acting Insulin

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Designing an Insulin Treatment Program: Physiologic Insulin Replacement

  • The ideal situation is to adopt a physiologic program. If you started a basal insulin and the patient now has postprandial hyperglycemia, you need to do what the body normally does: provide full-day insulin coverage. For all type 1 diabetes patients, this is a given: they will require insulin before each meal. For a type 2 diabetes patient, you will identify where the hyperglycemia occurred postprandially, and target that particular meal after looking at the meal composition and other issues that may contribute to postmeal glucose highs.

    In addition, type 2 diabetes gets worse in terms of hyperglycemia because of declining beta-cell function. Initially it is a loss of early insulin secretion, but eventually both early and late insulin secretion declines. Consequently, many of these patients gravitate towards a form of basal/bolus therapy.

  • Slide 30. Option: Physiologic Insulin Replacement Programs to Mimic a Normal Basal/Bolus Pattern

    Slide 30.

    Option: Physiologic Insulin Replacement Programs to Mimic a Normal Basal/Bolus Pattern

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  • This is a current model of basal/bolus therapy. We use either detemir or glargine as our basal insulin, and then we give a premeal bolus, any one of the very rapid-acting insulin analogs (aspart, lispro, and glulisine) that fit normal physiology much better. The peak is rapid, and almost coincides with what happens with normal insulin secretion. It is a very good tool for meal control.

    Remember, when we used regular insulin, patients had to take it 30 minutes, at least, before they ate? However, patients never waited 30 minutes; they took it just before they ate. With these insulins, you can take it and eat immediately. The danger is to take it and not eat; then you run the risk of becoming hypoglycemic, especially in type 1 patients.

  • Slide 31. Basal-Bolus Insulin Treatment With Insulin Analogs

    Slide 31.

    Basal-Bolus Insulin Treatment With Insulin Analogs

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  • There are also analog mixes, which lend themselves very nicely to a basal/bolus approach for appropriate patients. This is where clinical judgment comes into play, and the total picture is assessed. There are some patients who require postprandial control, but not necessarily basal/bolus therapy and all of its components. Analog mixes could be a very nice middle step for some of those patients. It is not recommended for use in type 1 diabetes.

  • Slide 32. Biphasic Insulin Analogs

    Slide 32.

    Biphasic Insulin Analogs

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  • Inhaled insulin has a profile much like lispro. We have no outcome studies that this insulin is superior. Most of the trials done to date are noninferiority trials, and it is equivalent in terms of the pharmacodynamics. It is not known if there will be improvement in glucose control.

  • Slide 33. Injected vs Inhaled Insulin Action Patterns: Considerations Beyond Method of Delivery

    Slide 33.

    Injected vs Inhaled Insulin Action Patterns: Considerations Beyond Method of Delivery

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  • All of the studies, in general, have confirmed using inhaled insulin for prandial coverage is effective; it depends on what the comparator is. If the comparator is regular insulin, inhaled insulin looks better. If the comparator is a fast-acting insulin analog, they are comparable. If the comparator to inhaled insulin monotherapy is two oral antidiabetes medications, insulin wins. If the comparison is a combination of oral medications vs inhaled insulin plus 2 oral medications, insulin plus orals win. The downside of some of these combinations is hypoglycemia. They do work; it is a matter of selecting the appropriate patient.

  • Slide 34. Option: Using Inhaled Insulin for Prandial Coverage: Summary of Clinical Efficacy Trials

    Slide 34.

    Option: Using Inhaled Insulin for Prandial Coverage: Summary of Clinical Efficacy Trials

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  • What are the indications for basal/bolus therapy? It is indicated in all type 1 patients and patients with type 2 diabetes, who as time goes on, become more insulin-deficient. There is a great deal of variability in their blood glucose levels; both postprandial and fasting levels go up. Remember, early in type 2 diabetes, there is postprandial hyperglycemia with the loss of early insulin secretion. Later in the disease there is fasting hyperglycemia, due to an overall decline in insulin production. These represent two different mechanisms, one at the liver for increased hepatic glucose output and the higher fasting glucose, and the other, decreased glucose utilization in muscle leading to postprandial hyperglycemia. And it takes much more insulin to put glucose into muscle than into fat. That is why postprandial glucose goes up early in type 2 diabetes.

    Intensive insulin therapy, especially insulin pumps, is being used more often in patients with type 1 diabetes and even in those with hypoglycemic problems, especially hypoglycemic unawareness, because the delivery of a single type of insulin can ameliorate the problem to a great extent. We use this for patients who want intensive therapy. You would be surprised that young patients say, "I want the best control I can get. The shots and fingersticks do not worry me. Give me what you think is the best therapy today."

  • Slide 35. Insulin Therapy: Indications for "Basal-Bolus" Treatment

    Slide 35.

    Insulin Therapy: Indications for "Basal-Bolus" Treatment

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  • When giving a patient an intensive insulin therapy program, years ago we would give them an algorithm, which is a predetermined range of blood glucose, and then we would calculate a dose for each meal based on the amount of carbohydrates they were eating. Patients just looked at the number and took a certain amount of insulin.

  • Slide 36. Sample Physiologic Insulin Replacement Algorithm: Premeal Rapid-Acting or Inhaled Insulin

    Slide 36.

    Sample Physiologic Insulin Replacement Algorithm: Premeal Rapid-Acting or Inhaled Insulin and Bedtime Basal Insulin

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  • We have now moved away from these fixed algorithms. If we are going to do basal/bolus therapy correctly, I think we must include carbohydrate counting and education on this. The best way to adjust insulin is based on carbohydrate content; the more carbohydrates, the more rapidly they are absorbed, the more insulin that will be required. Patients are making these modifications every meal, and it requires pre- and postmeal testing. This is the premium policy that we are now selling; the patient has much more input and greater flexibility.

    We will provide the tools to support that decision if patients are ready to make it. We will give them insulin-to-carbohydrate ratios. For instance, if you are having 2 slices of bread, and 1 slice of bread is 15 grams of carbohydrate requiring 1 unit, you will take 2 units of rapid acting insulin. More insulin-resistant patients will require a higher insulin dose per 15 grams of carbohydrate.

    We also provide correction factors. Patients with diabetes do not always start a meal at their glucose goal of 100 or 110 mg/dL. If it happens to be 250 mg/dL one day, for whatever reason, we give them a "correction factor" to help bring it down to 100 mg/dL. The standard that we use is 1 unit of insulin for every 50 mg/dL above the targeted glucose level. For a very insulin-resistant patient, 1 unit may result in a 20-mg/dL drop, and we adjust for that. Providing patients with these tools will give them the means to do this intensive therapy, and at the same time, achieve glycemic control on a daily basis, as well as lower A1C.

  • Slide 37. Carbohydrate Counting: Flexible Carbohydrate Plan

    Slide 37.

    Carbohydrate Counting: Flexible Carbohydrate Plan

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  • Essentially, we have a lot of tools in our toolbox. Just focusing on insulin, we have already made huge strides. We have effective insulin preparations, we have designer insulins, and now we have this cutting-edge new tool. We need to know where its place is going to be in our armamentarium, and as new players arrive, they also will find their place.

    But I think the most important thing clinically is getting the best possible control, which is reducing A1C, the surrogate marker for glycemic control, to less than 7%, and we can do that very safely. The program that one chooses must be one in which the patient can participate fully, or if they cannot, their caregivers will be able to.

    Insulin pens and inhaled insulin are viable options for prandial insulin delivery. Pens can also deliver long-acting basal insulins. In general, the acceptance has been very good with these devices.

    What about the primary care provider? I think one of the key messages I would leave you with is: do not delay the initiation of insulin therapy. You can always start basal insulin. If there is an isolated peak of hyperglycemia, you can use an injection of rapid-acting insulin, or inhaled insulin is an option. But the delay of insulin therapy has been the problem to date.

    Primary care providers can design insulin therapy programs, and if they are not comfortable doing that themselves, they can refer patients for evaluation. It can be a collaborative model, and if problems arise, someone can be there to help.

    With inhaled insulin, the challenge will be how to work out some of the other issues, such as lung function testing; who is going to interpret it, and who is going to monitor it? We will work our way through these issues because every new tool goes through a period of uncertainty and then finds its own little niche. I am sure inhaled insulin, like the ones to follow, has a place in the therapeutic armamentarium.

  • Summary

    Slide 38.


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