Insulin Regimens

Insulin treatment can range from the simple regimens based on one or two daily insulin injections (conventional insulin therapy) to the more complicated multiple daily insulin injection regimens (intensive insulin therapy) or the continuous subcutaneous insulin infusion (CSII).

Single Daily Insulin Injection It is the simpler and easier regimen to administer insulin. Some newly

diagnosed type 1 diabetic patients (with some degree of residual b-cell function) can achieve glycemic control with less intensive effort by means

of a single injection of lente or NPH insulin alone or combined with regular insulin. Type 2 diabetic patients, poorly controlled with diet and oral hypoglycemic drugs, can be treated with a single daily insulin injection (often a night injection of lente or NPH insulin will suffice), as well as older patients with impaired vision or physically disabled who may experience difficulties with injections. This regimen is also useful for individuals with limited motivation and poor compliance to the diabetic therapy. The initial insulin requirement can depend on several factors: (a) the current degree of hyperglycemia; (b) the dietary habit; (c) the amount of remaining endogenous insulin secretion; (d) the physical activity or exercise, and (e) the body weight or degree of obesity.

A total dose of intermediate-acting insulin of 0.5–0.7 units/kg has been suggested (usually from 20–30 to 40–50 units/day), with subsequent adjust- ments according to the glycemic values obtained 2–4 times daily (as well as according to the hypoglycemic episodes, the presence of urinary ketones and

the HbA 1c values). With large doses of intermediate-acting insulin, availability of insulin may be inappropriate at certain times and there is the risk of nocturnal hypoglycemia. For some patients, an insulin preparation consisting the HbA 1c values). With large doses of intermediate-acting insulin, availability of insulin may be inappropriate at certain times and there is the risk of nocturnal hypoglycemia. For some patients, an insulin preparation consisting

Twice-Daily Insulin Injection When a single dose is inadequate or produces hypoglycemia, twice-daily

injections of NPH insulin are frequently used in insulin-dependent diabetics. Most patients should use two daily injections of a mixture of intermediate- acting (2/3) and rapid-acting (1/3) human insulins before breakfast and dinner. It is a relatively simple regimen that provides a good insulin availability over

a 24-hour period, even if it may induce late afternoon and nocturnal hypoglycemia with pre-breakfast hyperglycemia. Twice-daily insulin regimen is little flexible, inasmuch as insulin must be given at the same time every day and meal times must also be kept constant.

Multiple Daily Insulin Injections (MDI ) The intensive treatment regimens (as opposed to the simpler conventional

regimens, described above) are not suitable for everyone and should be adopted in the appropriate patients. Intensive insulin therapy should be encouraged in type 1 diabetes without residual insulin secretion and when twice-daily insulin injections are no longer adequate. Recently, this regimen was also proposed for type 2 diabetics (particularly the younger patients with a life expectancy of 10–15 years or more). The scope is to obtain

a good glycemic control which may reduce the development of diabetic microangiopathy, as shown by the DCCT (Diabetes Control and Com- plications Trial) study. However, this insulin intensive regimen may favor weight gain. Moreover, it has been postulated in the past that enhanced insulinization may be associated with increased risk of mortality from cardio- vascular disease and it was suggested that chronic hyperinsulinemia may cancel the beneficial effects of the better glycemic control. However, more recent data (from the DCCT for type 1 diabetes and from UKPDS for type

2 patients – see chapter VI) allow us to exclude that intensive insulin therapy entails risk for macrovascular disease. An absolute indication for intensive therapy is pregnancy (see chapter XVIII on Managing Diabetes and Preg- nancy).

An optimal glycemic control requires that insulin delivery simulates the normal pattern of insulin secretion, which consists of continuous ‘basal’ insulin An optimal glycemic control requires that insulin delivery simulates the normal pattern of insulin secretion, which consists of continuous ‘basal’ insulin

(a) The simplest intensive regimen entails the use of three injections, regular and intermediate-acting insulin before breakfast, regular insulin before supper and intermediate-acting insulin at bedtime. This 3 times daily insulin dose regimen is useful in diabetic patients with frequent nocturnal hypoglycemia and pre-breakfast hyperglycemia. The primary disadvantage of this approach is that meal schedules must be fixed rather rigidly.

(b) Regular insulin before each meal and intermediate-acting insulin at bedtime (4 daily insulin doses). This regimen provides the greatest flexibility because regular insulin can be adjusted to cover each meal, avoiding postprandial hyperglycemia.

(c) Regular and intermediate-acting insulin before breakfast, regular insulin before lunch and supper, and intermediate-acting insulin at bedtime (4 daily insulin doses).

(d) Regular insulin before each meal and ultralente insulin in the morning (to replace basal insulin secretion) or subdivided before breakfast and before supper (4 daily insulin doses). It is less preferable to the (b) regimen because ultralente presents unexpected small peaks 15–24 h after injection.

Human insulin lispro is very appropriate for multiple injection therapy, especially in patients with marked postprandial hyperglycemia and nocturnal hypoglycemia or with a variable lifestyle. Patients on insulin lispro had significantly lower glucose levels following meals (however with the potentially unwanted result of a rise in preprandial glucose) and showed a reduction in the incidence of severe hypoglycemia by 30% (compared to regular human insulin). In patients treated with insulin lispro (compared to those treated with human regular insulin) there should be less need for snacks. The majority of patients on insulin lispro reported an improved quality of life. However, there are some ‘failures’ with this type of insulin, as a number of patients may appear unable to control their diabetes with insulin lispro. At present, insulin lispro should be used with caution in children under the age of 12 as well as in gestational diabetes or pregnancy, because of lack of experience.

Other, far too complex, multiple-injection regimens have also been suggested. Certainly, the adherence to therapy is less likely to occur when the program of treatment is far too complicated. Some patients object to such frequent needle injections and ask for changing from this insulin regimen to a simpler program. Pen devices or jet injectors filled with insulin (that are easy to carry) make the multiple daily insulin regimens better accepted.

It is advisable to use no more than two types of insulin. It is noteworthy that in some patients a morning fasting hyperglycemia (the dawn phenomenon) occurs, that depends on the hepatic glucose overproduction activated in the morning due to inadequate overnight delivery of insulin and a sleep- associated GH release. This phenomenon is most pronounced in type 1 diabetic patients for their inability to compensate by raising endogenous insulin secretion. The magnitude of the dawn phenomenon can be attenuated by designing insulin regimens which ensure that the effects of exogenous insulin do not peak in the middle of the night and then become dissipated by morning.

Some patients (about 1/3 of type 1 diabetic patients) may experience early in the course of disease a brief honeymoon period, during which there is a partial recovery of b-cell function and a transient or a prolonged fall in the exogenous insulin requirement (=0.5 U/kg/day). The honeymoon phenomenon may be due to the termination of a ‘stress’ episode (infections, etc.) that has anticipated the manifestation of diabetes in a subject with ongoing b-cell destruction process. Spontaneous remission is less frequent in children and adolescent or pubertal patients, and more frequent in adult postpubertal patients. A low residual insulin secretion (probably linked to a more aggressive destruction of b-cells) can be implicated in children while a low insulin sensitiv- ity (probably linked to the increased secretion of GH hormone) may be impor- tant in pubertal patients. The honeymoon should not be regarded as a signal to reduce efforts aimed at glycemic control, because optimized insulin therapy may help to preserve b-cell function. It is recommended to continue insulin treatment even at low doses (even 1–4 U/day), since this can preserve b-cell function and may favor the remission.

Continuous Subcutaneous Insulin Infusion (CSII ) In sufficiently motivated diabetic patients, an alternative that provides

a greater flexibility of insulin treatment (minimizing variations in its absorp- tion) is CSII, with which insulin delivery may somewhat mimic that occurring in nondiabetic individuals. Insulin delivery pumps may be implantable or portable (with ‘closed loop’ or ‘open loop’ insulin infusion systems). The CSII method administers rapid-acting insulin around the clock using a battery-powered (externally worn) infusion pump, that delivers basal rates continuously (usually 0.5–2.0 U/h) and can be programmed to vary the flow rate automatically, reducing the flow rate at 1.0–4.0 a.m. and increasing it to compensate for increased insulin requirements early in the morning. Before meals, insulin boluses are given by manually activating the pump, in amounts based on frequent blood glucose self-monitoring determinations. Usually, a

3- to 5-day hospital stay is required for learning to use the insulin pump,

Table 3. Problems limiting the use of CSII Interruption of insulin delivery (commonly due to insulin precipitation within the catheter)

that leads to rapid severe hyperglycemia and ketoacidosis (because there is no depot insulin and all insulin being used is short-acting)

Pump malfunction (a pump malfunction with insulin overdose can produce severe and even fatal hypoglycemia) Loss of battery charge Leakage from the catheter Empty insulin reservoir Needle displacement Local infections (such as abscesses at the catheter site, only occasionally reported)

and successively a health-care professional should be available 24 h/day to assist the patient. Most pumps contain a syringe or a reservoir filled with insulin attached to an infusion set consisting of a catheter and a 27-gauge needle which is inserted into subcutaneous tissue (preferably in the abdomen). Unfortunately, the CSII presents several problems that limit its use (table 3), and the patients with brittle diabetes (see below) may not be the best candidates for a successful use of CSII. Most modern pumps present alarm systems for the different pump problems. Some diabetic patients are absolutely incapable to safely employ the insulin pump and to use the appropriate infusion rates. The high cost is another relevant disadvantage of CSII.

Insulin Regimens