Steve V. Edelman, MD
Robert R. Henry, MD
Insulin-pump therapy has been traditionally used for people with Type 1 diabetes. People with Type 1 diabetes usually do not have insulin resistance: therefore, they require low basal rates and small insulin boluses….
Because Type 2 diabetics have the underlying defect of insulin resistance in addition to beta-cell failure, they have increased insulin requirements. Insulin-pump therapy is extremely valuable in patients with insulin-requiring Type 2 diabetes who have not achieved glycemic control with subcutaneous (SC) injections, who are experiencing wide fluctuations in blood glucose levels complicated by hypoglycemia, or who are seeking a more flexible lifestyle.
All of the benefits of pump therapy that are enjoyed by patients with Type 1 diabetes discussed previously also apply to people with Type 2 diabetes. There are other potential advantages to pump therapy. A patient with Type 2 diabetes should be treated with the minimal amount of insulin possible to improve glucose control because excess insulin administration could cause further weight gain. When the pump is used, the number of hypoglycemic events decreases. Therefore, there is less overeating to compensate for hypoglycemia and weight gain may be less of an issue.
Many older patients with the diagnosis of insulin-requiring Type 2 diabetes have true late-onset Type 1 diabetes. It has been documented in the literature that when large groups of patients with insulin-requiring Type 2 diabetes mellitus were tested for anti-GAD antibodies, approximately 5% to 8% were positive.
Such individuals are thinner at the time of diagnosis, generally do not respond well to oral agents, and require insulin, although they do not present with severe DKA. This condition is now formally called LADA. This is another group that could potentially benefit from insulin-pump therapy. In general, if a patient with insulin-requiring Type 2 diabetes cannot achieve glycemic control with an intensive insulin-injection regimen, insulin-pump therapy should be considered.
New Types of Insulin Preparations
Lispro (Humalog) was the first fast-acting insulin analogue introduced in 1995. It is an effective agent for improving glycemic control while minimizing delayed hypoglycemia. The rapid onset of action appears to be mainly due to its faster absorption (peaking at approximately 30 to 60 minutes as compared with 60 to 120 minutes for regular insulin) when injection is SC. Its unique absorption and action properties are the result of a reversal in the two adjacent amino acids: lysine at position 28 and proline at position 29 on the beta-chain.
Some of the drawbacks of the older regular insulin preparations have been their slow onset of action as well as delayed clearance, resulting in inefficient control of postprandial excursions in blood glucose levels. With the faster rise and fall of the serum insulin level following a lispro injection, it is easier to coordinate the timing of insulin injections with the subsequent meal. Another advantage to this fast-acting insulin is that it does not have as prolonged an action as the currently available regular insulin, thereby reducing the incidence of delayed hypoglycemic reactions.
Insulin aspart (Novolog) is another fast-acting insulin analogue developed by substituting proline with aspartate on the beta-chain of the insulin molecule. The substitution of proline with aspartic acid in insulin aspart reduces its tendency to form hexamers like regular insulin. Insulin aspart has more rapid absorption and faster onset of action, within 10 to 20 minutes, than regular insulin, although both are absorbed to a similar extent. Insulin aspart peaks between 1 and 3 hours and has a duration of action of 3 to 5 hours. Because of its rapid onset and short duration, insulin aspart should be used in regimens along with intermediate- or long-acting insulin or with external pumps for subcutaneous insulin infusion. It may also be administered intravenously if under close medical supervision to monitor blood glucose and potassium levels. Differences in pharmacodynamics between insulin aspart and regular human insulin are not associated with differences in overall glycemic control. Insulin aspart has been studied in the pediatric population and been found to be comparable with regular insulin. It is also available in a premixed 70/30 mix disposable pen.
Insulin glulisine (Apidra) is also a fast-acting insulin analogue that was developed by replacing the asparagine in position B3 by lysine, and lysine at position B29 by glutamic acid. Final stages of clinical trials have been completed and it has been approved for therapeutic use in insulin-requiring diabetics.
Insulin lispro and insulin aspart are also available in single premixed suspensions: Humalog Mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection); Humalog Mix 50/50 (50% insulin lispro protamine suspension and 50% insulin lispro injection); and NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection). Because of the rapid onset of action of these new mixtures, they can be given anytime within 15 minutes before a meal and also can be effective if taken 15 minutes after a meal. These new mixtures are available in easy-to-use disposable insulin pens, each holding 300 units insulin. Another premixed formulation, Novolin 70/30, contains 70% NPH insulin Isophane suspension and 30% regular insulin.
The benefits of using the premixed formulations containing the fast-acting insulin analogues include:
• Reduction of postprandial hyperglycemia with the use of lispro/aspart
• No need to wait 30 to 45 minutes between an injection and mealtime
• Improved dosing accuracy in a pen compared with a syringe
• Lowered incidence of delayed hypoglycemia with the shorter-acting lispro or aspart in the mixture.
Several studies have compared regimens of twice daily (prebreakfast and presupper) premixed dual peak formulations containing a fast-acting insulin analogue with once-daily basal insulin glargine. In one study in insulin-naïve patients with Type 2 diabetes who were not adequately controlled with MET monotherapy, twice daily Novolog Mix 70/30 plus MET achieved A1c targets in significantly more patients than once-daily insulin glargine plus MET. The incidence of minor hypoglycemia and weight gain were slightly higher with Novolog Mix 70/30. Another study in diabetic patients starting insulin therapy compared twice-daily Humalog Mix 75/25 plus MET and once-daily insulin glargine plus metformin. Again, more patients on Humalog 75/25 achieved an A1c <7% than those on glargine. The overall rate of hypoglycemia in the Humalog Mix 75/25 group also increased slightly with the exception of nocturnal hypoglycemia.
A third study in patients with Type 2 diabetes inadequately controlled with intermediate insulin or insulin plus oral agent combination therapy found that patients in the Humalog Mix 75/25 plus MET group improved A1c levels, lower PPG levels, and experienced fewer episodes of nocturnal hypoglycemia vs once-daily insulin glargine with MET.
The disadvantage of premixed insulin is that the ratio of fast-acting to intermediate-acting insulin is fixed. The intermediate-acting dose must be given at dinnertime rather than at bedtime and there is no coverage at lunch. In addition, a patient cannot use carbohydrate counting or a correction factor to adjust the dose. Patients with Type 2 diabetes new to insulin might be considered good candidates for these new mixtures. In addition, patients already on the older 70/30, NPH insulin alone, or oral agents but who remain out of control or who have delayed hypoglycemia may benefit from these mixtures.
Insulin detemir (Levemir) is the latest basal insulin to be approved for once- or twice-daily treatment of adult and pediatric patients with Type 1 diabetes and adult patients with Type 2 diabetes who require basal (longacting) insulin. Produced by recombinant DNA technology, it differs from human insulin in that one amino acid (threonine) has been omitted on one chain and a fatty acid has been attached to the other chain. Its slow absorption and long duration of action are mediated by its strong self-association and extensive binding with albumin (approximately 98% bound) respectively. Compared with NPH insulin, detemir has slower, more prolonged absorption. Insulin detemir has a dose-dependent onset of action ranging from 0.8 hours at the highest dose to 2 hours at the lowest dose. Its time action profile is relatively flat at with a duration of action that ranges from 5.7 hours at the lowest dose to 23.2 hours at the highest dose and a Cmax between 6 and 8 hours. Insulin detemir (100 units per mL [U-100]) is currently available in a 10-mL vial and a 3-mL prefilled disposable insulin pen that can deliver 1 to 60 units of insulin in 1-unit increments. The prolonged duration of action of insulin detemir (~6 to 23 hours, depending on dose) is mediated by slow absorption from the injection site and slow distribution to target tissues due to strong self-association and albumin binding. Clinical trials in which insulin detemir was compared with NPH insulin using a basal-bolus regimen in patients with Type 1 diabetes and patients with Type 2 diabetes who were insulin-naïve or receiving oral anti-hyperglycemic agents showed effects on A1c and blood glucose levels comparable to those with NPH insulin with somewhat less variation in blood glucose levels and somewhat less weight gain.
Insulin glargine (Lantus) is the first peakless long-acting basal insulin analogue. Produced by recombinant DNA technology, it differs from human insulin through a change in one amino acid on the alpha insulin chain and two amino acids on the beta chain. It exists in an acidic form and cannot be mixed in the same syringe with other insulins. After SC injection, insulin glargine forms microcrystalline precipitates that gradually release insulin. Glargine has its onset of action at 4 to 6 hours and a duration of action of >24 hours without a peak. The rate of absorption does not differ for different injection sites and the pharmacokinetics within subjects is fairly consistent. Initial studies in patients with both Type 1 and Type 2 diabetes mellitus have shown that the drug is effective when either regular insulin or insulin lispro is used as adjunctive mealtime insulin. Glargine has also been studied as an additive agent in patients with Type 2 diabetes who are taking oral agents. The Treat-to-Target Study is comparing the effects of NPH or glargine at bedtime in patients failing oral agents discussed above. Following are several clinical suggestions for glargine use.
- Switching a Patient from the Traditional Split-Mixed Regimen to Detemir or Glargine
The recommended changeover suggests that the total NPH or Lente dose be reduced by 20% to determine the nighttime dose of detemir or glargine. It is important, however, to remember that a fast-acting insulin should be used before each meal, including lunch, with this new regimen. The total amount of insulin on the new long-acting/fast-acting insulin regimen should approximate the total split-mixed regimen dose. An example would be a 29-year-old white male who is taking 15 units of NPH and 5 to 10 units of Humalog, Novolog, or Apidra before breakfast and 10 units of NPH and 5 to 10 units of Humalog, Novolog, or Apidra before dinner. We recommend starting with an initial detemir or glargine dose of approximately 20 units at bedtime but also add in a prelunch injection of Humalog, Novolog, or Apidra of 5 to 10 units. Further adjustment should be based on the results of premeal and postmeal SMBG.
- Switching a Patient from a Regimen of Ultralente Twice a Day Plus Fast-Acting Insulin (Multiple Daily Injections) to Detemir or Glargine
In this scenario, the conversion is slightly easier. Take the total Ultralente dose and subtract 0% to 5% to get the initial detemir or glargine dose. If the A1c value is fairly good on the Ultralente regimen, subtract 5%, and if the degree of control is not adequate, use the total Ultralente dose to calculate the detemir or glargine dose. The premeal doses of Humalog, Novolog, or Apidra that are being used would be the same.
- When Converting a Patient from an Insulin Pump to a Detemir or Glargine Regimen or Vice Versa
Patients with Type 2 diabetes are candidates for converting from an insulin pump or vice versa. To do so, we would take the amount of insulin used for the basal rate of the pump and use that for the initial detemir or glargine dose and vice versa when initiating pump therapy from a long-acting/fast-acting insulin regimen. In our experience, we have achieved fairly good success with using similar total doses without any reductions. Obviously, the premeal dose of Humalog, Novolog, or Apidra does not change when converting to this regimen. On the first night of the detemir or glargine injection when initiating pump therapy, we ask the patient to take the dose of long-acting insulin earlier in the evening, i.e., 5 PM or 6 PM, and continue the basal rate of the pump until bedtime in order to avoid hyperglycemia the next morning.
- Other Issues Regarding the Use of Glargine
It was originally recommended that glargine be taken at bedtime, although it is now approved to be taken at any time that is convenient for the patient. A patient who goes from an insulin pump to a glargine regimen may forget to take the injection of glargine at night during the first few weeks after initiating therapy, leading to morning hyperglycemia. Methods to avoid forgetting should be implemented, such as leaving a note or some type of reminder near the bedside clock or nightstand.
Glargine can cause burning when injected, although we have not found this to be a problem. Occasionally, a patient may state that he or she feels that glargine has a peak and is causing hypoglycemia to develop approximately 12 hours after injecting. If this is true, the time of injection can be changed, and the home glucose monitoring data should be reviewed after several days. A very small percentage of individuals will benefit from splitting the glargine dose. Splitting the dose of Lantus is rarely needed and should be based on home or continuous glucose monitoring results and not on an arbitrary dosage amount.
Complications of Insulin Therapy
Weight gain and hypoglycemia are the most frequently reported complications of insulin therapy. Both can be minimized with appropriate preventive measures and dosage adjustments. It is important to emphasize that the benefits of improved glycemic control far outweigh any adverse effects of weight gain in a patient with poorly controlled diabetes.
Hyperinsulinemia caused by large amounts of exogenous insulin can lead to marked increases in weight, which is a real concern in Type 2 diabetes. Obesity itself is an insulin-resistant state that contributes to a cycle of worsening insulin resistance, increasing insulin requirements, and further weight gain. Some patients, particularly the obese, may require large doses of insulin to normalize glycemia in order to overcome the insulin resistance that is typical of Type 2 diabetes. The additional exogenous insulin can result in hyperinsulinemia and an average increase in body weight of 3% to 9%. Excessive weight gain can be minimized by using the lowest possible dose of insulin to achieve target glycemic goals and encouraging the patient to decrease caloric intake and increase exercise. Insulin detemir has consistently demonstrated less weight gain compared with NPH insulin in clinical trials in patients with both Type 1 and Type 2 diabetes. Studies of patients with Type 2 diabetes have reported less weight gain with insulin detemir (up to 2.6 lb) than with NPH insulin (up to 6.2 lb).
The incidence of hypoglycemic reaction increases with insulin therapy, particularly intensive regimens, and the thin and the elderly are most affected by such episodes. Obese patients with Type 2 diabetes tend to have much less hypoglycemia than those with Type 1 diabetes.
Severe hypoglycemia is rare in obese patients with Type 2 diabetes and is usually related to causal factors such as:
• Over insulinization
• Unplanned strenuous physical activity
• Excessive alcohol
• Incorrect dose of insulin or oral agents taken by patient.
Frequent SMBG by the patient with adjustment in the dose or type of insulin can significantly reduce the likelihood of hypoglycemia.
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© Copyright 2010. Steven V. Edelman, MD, Robert R. Henry, MD, Professional Communications, Inc. All rights reserved.
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