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.
BASAL VS PRANDIAL INSULIN
Once-daily insulin injection is relatively convenient, but it comes with a limitation: it does not adequately control postprandial hyperglycemia. A solution is insulin before meals, ie, prandial insulin.
Kazda et al19 compared three regimens in patients not taking oral hypoglycemic agents: rapid-acting insulin lispro (Humalog) before each meal, a mix of 50% lispro and 50% protamine lispro (Humalog Mix 50/50) (the protamine delays its release) before each meal, and glargine at bedtime. The absolute change in hemoglobin A1c was −0.3% in the glargine group, −1.1% in the lispro group, and −1.2% in the lispro mix group. The glargine group had better control of fasting glucose.
Similar advantages of better glycemic control and fewer nocturnal hypoglycemic episodes were seen in trials of a mixture of 25% lispro and 75% protamine lispro before meals compared with glargine insulin in patients on simultaneous treatment with oral hypoglycemic agents.20,21 Buse et al21 reported that more patients achieved a hemoglobin A1c level below 7% with this lispro mix (47%) than with glargine (40%). The absolute difference in mean hemoglobin A1c between the two groups was minimal, although it reached statistical significance. As expected, weight gain was less in the glargine group.21
Kann et al22 reported that glycemic control was also better with a mixture of 30% aspart and 70% protamine aspart (NovoLog Mix 70/30) twice a day along with metformin than with glargine insulin once a day along with oral glimepiride, a sulfonylurea. Further, in this study, weight gain was noted in the glargine-glimepiride group only.22 Therefore, the advantage of less weight gain has not been always reproducible in glargine studies.
Comment. These studies point to the contribution of postprandial glucose to hemoglobin A1c.23–25 In patients with satisfactory glycemic control, the postprandial glucose level seems to be the major contributor to hemoglobin A1c. When glycemic control worsens, the contribution of fasting glucose to hemoglobin A1c increases.23
Premixed insulins (lispro mix and aspart mix) provide basal coverage and control postprandial hyperglycemia. Therefore, prandial premixed insulin therapy is expected to be superior to basal insulin therapy. Premixed insulin could be considered as a simplified basal-bolus regimen (see below).
The superiority of prandial (rapid-acting) insulin alone over basal insulin therapy, as seen in the study by Kazda et al,19 has not been reproducible in other studies. For example, in one study, once-daily glargine resulted in a similar improvement in hemoglobin A1c, a lower rate of hypoglycemic episodes, and greater patient satisfaction with treatment compared with lispro insulin before meals.26 This issue remains debatable because all the trials have been open-label and thus are subject to limitations.
The main lesson is that either glargine or lispro monotherapy is a reasonable option and results in better glycemic control in patients for whom two oral hypoglycemic agents have failed. Further, both fasting and postprandial hyperglycemia are important to address. In patients with severe hyperglycemia, a combination of prandial and basal insulin may be indicated. One would expect neither basal nor prandial (bolus) insulin to be adequate in this situation.
In conclusion, adding basal insulin to oral hypoglycemic agents is a reasonable option in the advancement of diabetes therapy and has become a common way to introduce insulin. It is simple and less labor-intensive for patients and medical groups than a basal-bolus regimen. Patients usually find it acceptable. The future availability of an easy-to-deliver, safe, and effective prandial insulin may change the current treatment paradigm; several newer prandial insulins are under investigation.
In advanced diabetes, both prandial and fasting glucose levels are crucial to address. Some patients may need to be started on both basal and prandial insulin simultaneously, depending on their degree of hyperglycemia, the duration of diabetes, coexisting medical conditions, and the goal of glycemic control.
BASAL-BOLUS INSULIN REGIMENS
In the advanced stages of type 2 diabetes, as insulin deficiency worsens, patients need to start giving themselves injections of a rapid-acting insulin—regular, lispro, aspart, or glulisine (Apidra) before meals, in addition to once- or twice-daily basal insulin injections. Such a “basal-bolus” regimen could also be used for newly diagnosed patients presenting with severe hyperglycemia. In addition, some patients on basal insulin plus oral hypoglycemic drugs may develop contraindications to their oral drugs. Adding bolus insulin becomes the main option for these patients too.
For others, a basal-bolus regimen might be chosen purely because of cost. For example, a regimen of NPH and regular insulin (multiple daily injections or premixed) would be significantly less expensive than multiple oral hypoglycemic agents.
Currently, only a few classes of oral hypoglycemic drugs are available in generic formulations. For example, generic glimeperide and metformin cost as little as $4 to $12 per month, while the costs of brand-name oral hypoglycemic agents are in the range of $170 to $200 per month. In contrast, premixed NPH plus regular insulin such as Novolin 70/30 and Humulin 70/30 cost between $22 and $70 per vial.
A basal-bolus regimen should provide 50% of the total daily insulin in the form of basal insulin. A regimen of 50% basal and 50% bolus seemed to provide better glycemic control than a regimen of 35% basal and 65% bolus in several studies.27,28
In patients already taking a single daily dose of basal insulin along with oral hypoglycemic agents, the dosage of basal insulin is usually raised gradually until adequate glycemic control is achieved. A main question is when to add prandial insulin. There is no clear cutoff for a basal insulin dosage at which prandial insulin should be added.
In the Treat-to-Target Trial,29 almost 60% of patients achieved a hemoglobin A1c level of 7% or less with the addition of either glargine or NPH insulin (basal insulin only) to oral hypoglycemic agents during 24 weeks of follow-up. As expected, glargine caused less nocturnal hypoglycemia. Fewer than half the patients who achieved a hemoglobin A1c level less than 7% had no documented nocturnal hypoglycemia (33% of glargine-treated patients and 27% of NPH-treated patients).
Type 2 diabetes is progressive1; over time, patients treated with once-daily basal insulin often require multiple daily injections.
Adding prandial to basal insulin clearly results in better glycemic control and less glucose variability.19,20,22,30–33 Two major factors in deciding to start prandial insulin are the degree of hyperglycemia and the patient’s acceptance of multiple daily injections. The higher the blood glucose levels, the sooner prandial insulin should be added, especially if hyperglycemia is influencing the prognosis of a coexisting condition or a diabetic complication (eg, an infected foot ulcer).
Adding prandial insulin should be also considered if the dosage of basal insulin has progressively been increased and the hemoglobin A1c level is not improving, especially if a patient has both inadequate glycemic control and frequent hypoglycemia, or if the morning glucose level is within the desired range (indicating there is no room for a further increase in the basal insulin dose) in association with inadequate control of hemoglobin A1c.
