Insulin treatment for type 2 diabetes: When to start, which to use
ABSTRACTIn type 2 diabetes mellitus, oral hypoglycemic agents and analogues of glucagon-like peptide-1 provide adequate glycemic control early in the disease. Insulin therapy becomes necessary for those with advanced disease. Further, some experts recommend electively starting insulin therapy in early diabetes. This review addresses practical approaches to insulin therapy, particularly when it is indicated and which regimen to use.
KEY POINTS
- Whether to start insulin therapy and which regimen to use depend on a number of factors, including the patient’s acceptance and willingness to adhere to the therapy.
- A common way to start is to add a once-daily dose of a long-acting insulin at bedtime (basal insulin) to the patient’s antidiabetic regimen.
- Basal regimens do not control postprandial hyperglycemia very well. Another option is to take a long-acting (basal) insulin along with a rapid-acting (prandial or bolus) insulin before meals. Multiple formulations of premixed insulins are available and are convenient to use among new users.
- Basal-bolus regimens, which involve injections of rapid-acting insulin before meals and long-acting insulin at bedtime, are gaining popularity. Their cost and the number of injections may affect patient acceptance of this treatment.
What is the best basal insulin for a basal-bolus regimen?
Glargine and detemir were shown to be equally effective as the basal component of a basal-bolus regimen.34,35 Findings were similar to those of studies comparing NPH, detemir, and glargine added, by themselves, to oral hypoglycemic agents. When possible, either glargine or detemir is favored because of less hypoglycemia and less weight gain than with NPH. Weight gain is the least with detemir.
Adding prandial insulin to a basal regimen
In general, whether to add prandial insulin can be decided on the basis of the patient’s record of blood glucose monitoring. Insulin could be added before breakfast if the pre-lunch glucose level is elevated, or before lunch if the dinnertime blood glucose level is elevated, or before dinner if the bedtime blood glucose level is elevated—or a combination of these. Prandial insulin can be started at a low dose (4–6 units) and increased gradually.
In the case of poor glycemic control on a high dosage of basal insulin, a reasonable first step would be to change the regimen to a basal-bolus regimen (about 50% basal and 50% bolus) with no change or a small decrease in the total daily dosage of insulin to avoid hypoglycemia. For example, in a patient on 80 units of glargine or detemir insulin who has inadequate control, the regimen could be changed to 35 units of either glargine or detemir and 10 to 12 units of lispro, aspart, or glulisine before each meal as the bolus component.
Further adjustments of the insulin dosage can be made according to the results of glucose monitoring before each meal and at bedtime. In all case scenarios, the insulin regimen should be re-evaluated routinely during the advancement of therapy from single daily injection of basal insulin to multiple daily injections. Redistribution of total insulin dosage to 50% basal and 50% bolus (divided into three doses before meals) should be considered for patients who continue to have fluctuations of glucose levels, inadequate control, or frequent hypoglycemia. This ratio seems to provide better control for most patients.27,28
Starting with a basal-bolus regimen
For patients new to insulin who are starting a basal-bolus regimen, a dosage based on total body weight could be considered. The requirements vary significantly based on dietary management, level of physical activity, stress (especially illnesses), use of oral hypoglycemic agents, and degree of hyperglycemia.
A lower dosage of insulin (0.2 units per kg) should be considered for people with mild stress, with milder hyperglycemia, or on treatment with oral hypoglycemic agents. Elderly patients and patients with renal or liver failure are at higher risk of hypoglycemia and should also receive a lower dosage of insulin, at least to start with.
Others could be started on a dosage of 0.3 to 0.5 units/kg. Fifty percent of the calculated dosage could be given as basal insulin and 50% given as bolus (divided into three doses, before meals). Subsequently, the dosage would need to be titrated on the basis of the record of glucose monitoring.
Choosing a prandial insulin
Rapid-acting insulin analogues (lispro, aspart, and glulisine) control postprandial glucose levels better than regular insulin and cause less hypoglycemia. Their pharmacokinetics enable them to be taken within a few minutes of the start of a meal, or even after the meal if the patient forgets to take an injection before the meal.
For example, in one study,36 taking aspart immediately before the meal provided better glycemic control than taking regular insulin 30 minutes before meals. In a basal-bolus regimen, the use of aspart along with detemir resulted in glycemic control similar to that provided by twice-daily NPH and regular insulin, with less hypoglycemia.37
The dosage of prandial insulin can be adjusted according to the amount of carbohydrates in each meal (the insulin-to-carbohydrate ratio), as in patients with type 1 diabetes. This approach was associated with less weight gain.38
IS THERE STILL A ROLE FOR PREMIXED INSULIN PREPARATIONS?
Basal-bolus insulin regimens have gained popularity because the prandial doses can easily be adjusted according to carbohydrate intake, glucose level (on a sliding scale), variations in meal time, missed meals (eg, when having a procedure), and exercise. For example, the dose of prandial insulin can be reduced if the patient expects to exercise within 2 or 3 hours after the meal.
Some patients may not accept giving themselves four or five injections per day with a basal-bolus regimen. They may accept a simpler regimen, ie, giving themselves three injections of a premixed insulin per day, one before each meal.
Compared with a basal-bolus regimen, the possibility of achieving adequate glycemic control using lispro mix (50% lispro, 50% lispro protamine suspension) before meals seemed to depend on the goal of glycemic control. Its use in one study showed similar ability to achieve hemoglobin A1c less than 7.5% compared with a basal-bolus regimen of glargine and lispro. For a goal hemoglobin A1c level of less than 7%, the use of glargine and lispro was superior. The rate of hypoglycemia was similar with both strategies.39 These findings imply that the goal hemoglobin A1c should be more relaxed (< 7.5%) when using lispro mix (50% lispro) three times daily before meals.
Biphasic insulin aspart (a mix of aspart and protamine aspart) given three times daily provided similar improvement in glycemic control with no difference in the frequency of hypoglycemia compared with a basal-bolus regimen of NPH and aspart.40 Further, the use of biphasic insulin aspart seemed to provide better glycemic control with less weight gain compared with premixed human insulin (70% NPH, 30% regular insulin).41
Therefore, simpler premixed insulin regimens remain reasonable options for selected patients who do not accept a more complex insulin regimen (basal-bolus) or cannot adhere to it for any reason, especially if premixed insulin is given before meals three times daily. In fact, recent studies have focused on comparing premixed insulin three times daily with basal-bolus regimens (detemir or glargine as basal insulin along with pre-meal insulin analogue).
Glycemic control is harder to achieve with premixed insulin twice daily, mainly because of a higher frequency of hypoglycemia.42 In Europe, the use of premixed insulin three times daily is a popular option, whereas in the United States, a twice-daily schedule has been more common.
