Did you arrive here by via search engine?
Click here to view the original version of this article

Click to Print This Page
(This section will not print)

Insulin Therapy for Type 2 Diabetes

Course Authors

Eli Ipp, M.D.

In the past three years, Dr. Ipp has received grant/research support from Pfizer, Inc., R.W. Johnson, and Novo-Nordisk. He has served as a consultant for Novo-Nordisk, SmithKline Beecham Pharmaceutical and Hoechst Marion Roussel. Dr Ipp has also served on the Speakers' Bureau for Novo-Nordisk.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Discuss the difficulties encountered in switching type 2 diabetic patients to insulin

  • List the indications for insulin therapy in type 2 diabetes

  • Discuss the different insulins available for treatment of type 2 diabetes

  • Discuss combination therapy with oral agents and insulin in type 2 diabetes.

 

Patients with Type 2 Diabetes Switch to Insulin Therapy with Much Reluctance

Typically, when discussing the management of type 2 diabetes, most emphasis is placed upon the use of oral agents. In recent years, pathogenesis-based treatment has encouraged an approach that is more conceptually attractive.

Unlike the situation in type 1 diabetes, type 2 patients know that there are alternatives to insulin therapy.

Putting a patient on insulin is a last resort in most circumstances, and from the doctor's and patient's perspectives it is often regarded as evidence of failure. Neither attempts at life-style changes nor the use of oral agents have prevented the patient from reaching the ultimate step that is so often associated with the concept of "severe" diabetes in the minds of patients and their families. We particularly face an important cultural barrier in the Los Angeles area: no patient celebrates having to start insulin therapy, but amongst many Mexican-American patients we treat, we often encounter "folklore" that states that insulin treatment is the cause of blindness and kidney failure. The likely explanation for this misconception is not difficult to understand, but it is extremely difficult to explain this away to many of our patients.

Physicians Have Also Been Reluctant Users of Insulin in Type 2 Diabetes

The switch to insulin therapy is a big step, and one that is difficult for physicians as well. There are probably two main reasons for the reluctance of many physicians to place their type 2 patients on insulin. First, there is the realization that with the start of insulin, we enter into a vicious cycle: weight gain → deteriorating glucose control → requirement for larger insulin doses → further weight gain and so on. Second is the fear of accelerating atherosclerosis with insulin therapy. We have come to understand that hyperinsulinemia is a risk factor for atherosclerotic heart disease, and this has been extrapolated to the hyperinsulinemia of exogenous insulin therapy.

For those worried about the "vicious cycle," we need to emphasize the fact that glucose control is so poor at the time of starting insulin that there really is no choice but to move on and treat with insulin. Combined therapy with insulin sensitizers (see later) is also a possible solution to the vicious cycle of weight gain. Concern about atherosclerosis has, to some extent, been put to rest by the UKPDS (UK Prospective Diabetes Study), where insulin therapy for type 2 diabetes was not associated with an increase in atherosclerotic cardiovascular events. In fact, improved diabetes control had a small, statistically borderline positive influence - and insulin treatment had the same effect as the oral agents used.

The Diabetes Educator Has an Important Role

Switching patients to insulin, therefore, requires explanation of all these issues. As we discussed, the role of the diabetes educator is invaluable in preparing the patient for this change in therapy and also helping them deal with the consequences once treatment has begun. The switch to insulin is another opportunity to review with the patient their prior regimen. Has diet and exercise been maximized? Is the patient really taking the oral agents as prescribed? This can often proceed even as the patient is begun on insulin, especially if combination therapy with bedtime insulin and daytime orals is used (see below).

Indications for Insulin Use in Type 2 Diabetes

Primary Indication for Insulin Therapy in Type 2 Diabetes

The primary indication for insulin therapy is progressive beta cell failure -- the natural history of type 2 diabetes dictates this eventual outcome for these patients. Successful attempts to treat with life-style changes and/or oral agents may have some influence upon the rate of decline. For example, in animal studies of type 2 diabetes, insulin sensitizers appear to delay or prevent the histological ravages of diabetes on the beta cell. It is unknown whether this applies to human disease. However, it is clear that the natural history of the disorder is progressive and that insulin secretion fails with time, leading to failure of all oral agents that have been studied for long enough to test this. Many patients with type 2 diabetes will, therefore, go on to receiving insulin treatment. The UKPDS (UK Prospective Diabetes Study) has delineated this for all but the most recent medications that were not available for testing during that comprehensive study. It, therefore, follows that, if the beta cell mass is failing to provide enough insulin to maintain glucose control with the help of the oral agents, insulin replacement must be an option.

Indications for Insulin Therapy - Not All Are Related to Poor Glycemic Control

The major indication for insulin use in type 2 diabetes is beta cell insufficiency and the failure to respond to oral agents, which leads to unacceptable glycemic control. However, there are also other indications for insulin treatment that do not necessarily rely on a therapeutic trial of oral agents to determine the state of beta cell function, and are, therefore, not necessarily related to glycemic control. These include:

  1. Pregnancy. Insulin does not cross the placenta and is known to be a safe treatment in pregnancy. Oral agents are contraindicated in pregnancy.
  2. Severe hypertriglyceridemia. When serum triglycerides are close to or above 1000 mg/dl, the threshold for acute pancreatitis, insulin therapy is helpful to clear triglycerides by stimulating lipoprotein lipase activity. This is useful at least until blood glucose is under control and diet/ hypolipidemic agents are effective to maintain triglycerides at safer levels.
  3. Wasting states. Insulin may be able to contribute an anabolic influence, in addition to its traditional action to improve blood glucose control, for patients with HIV disease and cancer. The overall state of the patient and their willingness and ability to deal with insulin need to be taken into account, though I generally encourage these patients to take insulin, unless their diabetes is already very well controlled on oral agents
  4. LADA (latent autoimmune diabetes in adults). Five percent of all patients with apparent type 2 diabetes turn out to be autoantibody positive and a majority of these later require insulin treatment. These are thought to be patients with type 1 diabetes that first presents as a disease of adults. LADA is typically associated with a slow course of autoimmune destruction of beta cells and, thus, with a prolonged period (often many years) where patients have enough residual beta cell function that their disease resembles type 2 diabetes. These patients, therefore, respond to oral agents and can even be well controlled.

    The rationale for insulin treatment in this situation is not just to anticipate the inevitable, but is based upon the beneficial effects of insulin as a possible immune modulator in type 1 diabetes. This is the basic principle behind the DPT1 trial (the NIH-sponsored, multicenter Prevention of Type 1 Diabetes Trial) that is currently underway. In this large randomized clinical trial, patients at risk for type 1 diabetes are given insulin before frank diabetes develops as the primary approach to prevention. Until the results are available, it makes good sense to use insulin prior to the development of outright beta cell failure in patients with this autoimmune destructive disease. Insulin therapy is an attempt to preserve their beta cell function for as long as possible -- after all, these patients will eventually need insulin anyway. Retained beta cell function makes glycemic control much easier for patients with autoimmune diabetes and should be a therapeutic target in these patients.

  5. Post-myocardial infarction (M.I.). Recent data indicate that there might be a role for tight diabetes control during and after an acute M.I. in patients with type 2 diabetes. Trials demonstrated reduced mortality in the first year after an M.I.; the treatment was with insulin. Insulin may not be the only way to achieve tight control in this situation, this remains to be shown. However, it appears that tight control should be achieved from the time of hospitalization for the M.I.. Insulin is the most effective way to achieve tight control in most patients who are hospitalized, due to the stress of illness at that time. This is an area in which an indication for insulin therapy cannot be considered to be absolute until more data are available, but it is mentioned here to be taken into account as an additional factor in type 2 patients in whom we may be considering insulin as a therapeutic option.

Types of Insulin Available

This Cyberounds® conference will not go into the detailed pharmacology of the insulins. It is assumed that this information is known or readily available in standard textbooks or libraries. We will begin with a brief survey of the well-known insulins and, then, discuss some of the newer insulins.

  1. Regular insulin. This is the old standby therapy that essentially has been available since the 1920s, though its purity has dramatically improved over the years, particularly since its manufacture by recombinant DNA techniques. Insulin was the first molecule to be synthesized using DNA techniques that was placed in the therapeutic market. It is rapidly absorbed from the subcutaneous area and has been the mainstay of therapy to cover meal-induced increases of glucose.
  2. Longer acting insulins. These were introduced in the 1950s to make life easier for patients with diabetes because it was envisaged that a once-a-day injection would simplify management. This is clearly not the case in our hindsight of today, where an argument is made that even two shots per day is insufficient. The most commonly used insulins in this group are intermediate-acting insulins, NPH (neutral protamine Hagedorn) and the lente series of insulins. Ultralente was a long-acting insulin, but since human ultralente (formulated differently to slow down its absorption from the subcutaneous depot) has been available, the shorter duration of action of the human type has made its pharmacokinetics tend to resemble NPH --it thus needs to be injected twice daily in order to provide adequate coverage throughout the day.
  3. Insulin analogues. These insulins were developed to provide unique characteristics that are unavailable with the standard insulins.
    1. rapidly absorbed insulin. A number of modified insulins have been developed by the pharmaceutical companies to allow more rapid absorption of insulin from subcutaneous sites. One such insulin, currently approved by the FDA in the U.S. at this time, is lispro. Designed to prevent the aggregation of insulin with zinc, the subcutaneous insulin depot is in a monomer form and is, therefore, rapidly absorbed, so that it reaches a peak within an hour of injection instead of two hours. The rapid absorption enables lispro to be injected with meals and without the 30-45 minute delay in eating recommended after injection of regular insulin. This is an important advance in the ease of diabetes management -- we all recognize that the goal of improved adherence is more likely to be achieved when day-to-day activities are simpler for people with diabetes. Furthermore, lispro is particularly important for the management of diabetes in small children. It is difficult to explain to a child why they should wait to eat when they are hungry, necessary when regular insulin was used, but not when patients use lispro. The ability to inject without a prior waiting period is also useful in adults in situations when the quantity of food ingested at a meal is unpredictable. In small children or in adults with abdominal disorders, where nausea or anorexia may affect the ability to complete a meal, hypoglycemia can be prevented by titrating the dose of rapidly absorbable insulin analogue according to the quantity eaten -- and injected immediately after the meal. Studies have shown adequate glucose control even when the analogue is given immediately after meals.
    2. ultra-long acting insulin. These are insulins designed to be injected once a day. These insulins, none of which is approved yet for human use, provide the equivalent of continuous basal insulin. Ultra-long acting insulins are meant to be used together with other short acting agents which provide coverage for meal-induced glucose increments. Other ultra-long acting insulins are also being developed that are not insulin analogues, but are attached to molecules that either slow their release after absorption into the circulation or retard their absorption from subcutaneous depots. These will be similar to the old PZI (protamine zinc insulin).
  4. U500 insulin. This is not a new insulin; though it is a rarely used form of insulin (it contains 500 units/ml) and deserves wider adoption, especially among patients who have severe insulin resistance. Very rarely, doses of over 1,000 units per day are prescribed in patients with the syndromes of insulin resistance with acanthosis nigricans. But it is not only in these most insulin resistant patients that we should be using this form of insulin. Any patient who requires more than 100 units of insulin (combined short and long acting) will either need to have two shots or must use U500 insulin. Physicians are reluctant to reach such doses of insulin, i.e., usually over 200 units per day. But some very obese and insulin resistant patients require these dose levels, and they should be switched to U500 when necessary. U500 insulin is a form of regular insulin and it illustrates an important principle: that high concentrations in the insulin subcutaneous depot delay absorption from this site. It is, therefore, not necessary to add any other type of insulin. U500 provides both early and late release of insulin and, thus, can be injected twice daily.

    The use of U500 creates practical problems, however. Because there is no syringe for U500, it must be injected using U100 syringes. One has to distinguish, therefore, between "syringe units" and "dose units." Dose units are 5-fold greater than syringe units because 100 syringe units (1 ml) is equal to 500 dose units (500 units/ml). Patients have to be well-trained to understand the difference; our experience is that patients often have to explain this to physicians and nurses who are unfamiliar with this type of insulin if they arrive from another hospital. U500 is very effective when used appropriately.

  5. Alternate delivery systems for insulin. Insulin for use in type 2 diabetes can also be delivered in alternate ways. These delivery systems were designed for people with type 1 diabetes, but they are occasionally used in type 2 diabetes as well. Some patients use insulin infusion pumps; both external and implanted pumps have been used in type 2 diabetes. Nasal delivery of aerosolized insulin is another method of delivery of insulin that looks quite promising in terms of biological action. Long-term effects on the lung are still being investigated.
  6. Combination with oral agents. Insulin has been used in combination with oral agents for many years. Use with sulfonylureas achieved similar diabetes control as insulin alone, and reduced the insulin doses by up to 30%. The logic for insulin's use with sulfonylureas is somewhat lacking. This is because the effect of sulfonylureas is to simultaneously increase insulin secretion and delay insulin metabolism. This can be more cheaply achieved with insulin alone. The argument for combined therapy with insulin sensitizers or metformin is stronger since there is the potential to not only reduce insulin dose but also to affect insulin resistance and possibly the development of the obesity-induced vicious cycle, referred to above. A recent study of thiazolidinediones (TZDs) and metformin indicates that TZDs are more effective in reducing the insulin dose when used in combined therapy with insulin in type 2 diabetes. TZDs have a stronger effect to enhance insulin action during insulin therapy. Long-term weight effects of combined therapy are unclear. Many physicians who use combination therapy feel that it is a most effective way of inducing improved diabetes control in difficult-to-treat type 2 patients who are already on insulin.
  7. Initiating insulin therapy in patients on oral agents. A convenient way of switching patients who are on oral agents to insulin is to begin with an overnight dose of NPH or lente. The insulin is given at bedtime so as to reduce plasma glucose levels overnight. In this way, the oral agents maintain the patient's blood glucose during the day, after starting with normalized blood glucose levels in the morning. The advantage of this method is, first, that it works well in some patients and, second, that it is a convenient way for patients to get used to using insulin while they still have the security of taking their familiar oral agents. This approach requires another blood glucose measurement at bedtime (and, occasionally, during the night if hypoglycemia is suspected), but otherwise it is a fairly easy change for the patients to make. Unfortunately, it is not sufficient in some patients, and in many is only temporarily effective. If this combination is not effective, daytime insulin will also be required, and as with type 1 diabetes, at least two shots of insulin per day will be needed for adequate glycemic control. Retaining oral agents once the patient is on split dose daily insulin is only justified if the patient is on one oral agent (which of these to use is discussed above).

Complications of Insulin Therapy in Type 2 Diabetes

Insulin Side Effects Are What You Would Expect

The complications of insulin therapy in type 2 diabetes are similar to those in type 1 diabetes, namely hypoglycemia and weight gain. The UKPDS showed that insulin therapy and sulfonylurea therapy each had a similar frequency of hypoglycemia to begin with in newly diagnosed patients with type 2 diabetes. As time went by, insulin was more likely to induce low blood glucose than the other treatments. In the case of severe hypoglycemia (where another person was necessary to help the patient with the hypoglycemic episode), insulin was two to four times more likely to be the cause than the oral agents. Weight gain is a problem with all methods of treatment of type 2 diabetes and, according to the UKPDS, insulin was only marginally more likely to induce weight gain compared with the sulfonylureas. Metformin was the only oral agent that was not associated with more weight gain than control policy.