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Insulin in type 2 diabetes
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Insulin is the most effective agent at lowering glucose and plays an integral role in the treatment of type 2 diabetes. Although, in the past, insulin was often reserved as last-line therapy, current evidence suggests that aggressive lowering of glucose, especially with insulin, in newly diagnosed diabetes can result in sustained glucose control. Current consensus guidelines recommend lifestyle intervention and metformin at diagnosis. In patients unable to reach goals with this approach, well-validated tier-1 therapies include the addition of basal insulin or a sulfonylurea. Insulin therapy can then be intensified by the addition of prandial insulin when necessary.
Holman et al recently conducted a study to compare insulin regimens in patients with type 2 diabetes who were uncontrolled when assigned to oral therapy. The researchers compared three insulin regimens in 708 patients with type 2 diabetes during a three-year period. Five hundred seventy-eight patients completed the three years. All patients had an HbA1c between 7% and 10% despite being assigned to maximally tolerated doses of metformin and a sulfonylurea for at least four months. A history of thiazolidinedione use or triple oral antidiabetic therapy were exclusion criteria. Patients were randomly assigned to one of three insulin regimens. These regimens were twice-daily biphasic insulin aspart/insulin aspart protamine; three times daily prandial insulin aspart; or once- or twice-daily insulin detemir (Levemir, Novo Nordisk).
During the first year of the study, if HbA1c was ≥10% or ≥8% two consecutive times after 24 weeks in the study, sulfonylurea therapy was replaced by a second insulin, either prandial or basal, depending on initial insulin use. This was also done in patients whose HbA1c remained ≥6.5% further along in the study.
The primary outcome was change in HbA1c. After three years, the median HbA1c was 7.1% in the biphasic insulin group, 6.8% in the prandial insulin group and 6.9% in the basal insulin group. There was no significant difference in HbA1c among the three groups. The mean HbA1c reductions in the three insulin groups were 1.3% for biphasic, 1.4% for prandial and 1.2% for basal.
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The researchers identified numerous secondary outcomes, including but not limited to those reaching HbA1c goals, changes in glucose, weight changes, insulin doses, hypoglycemic events, and changes in blood pressure and cholesterol. Significantly more patients in the prandial (67.4%) and basal (63.2%) groups reached an HbA1c ≤7% as compared with the biphasic group (49.4%). Similar results were seen when comparing those patients who reached an HbA1c ≤6.5%. The prandial insulin group had the largest mean reduction in all self-monitored glucose readings (excluding 3 a.m. readings), with a mean reduction of 67 mg/dL. No significant differences in fasting glucose readings were observed among the three groups.
The prandial group had the largest reduction in postprandial glucose readings, including a significant reduction when compared with the biphasic group. Mean weight increased in all three groups as follows: biphasic, 5.7 kg; prandial, 6.4 kg; and basal, 3.6 kg. Insulin doses also increased in all three groups throughout the study, although the biphasic group saw the smallest increase in doses. Overall rates of hypoglycemia were highest in the prandial group and lowest in the basal group. There were no significant changes in BP or cholesterol among the three groups. The biphasic group experienced the highest rates of adverse events (44.7%) as compared with 33.1% for the prandial group and 33.3% for the basal group.
The researchers indicated that the basal group had the lowest weight gains and hypoglycemic events. They speculated that the cause of fewer patients in the biphasic group reaching HbA1c goals may have been due to less flexibility with those types of fixed-ratio insulin formulations. The results of this study provide support to current guidelines that suggest adding basal insulin to oral therapy as a means of introducing insulin in patients not reaching therapeutic goals. Insulin can then be intensified by addition of prandial insulin, as was done in this study.
Basal insulin is often introduced at a dose of 10 U to 20 U once daily or 0.2 U/kg to 0.3 U/kg once daily. Doses may then be titrated as often as every three days until the desired fasting blood glucose levels are obtained. These frequent office visits can be difficult for the patient and the provider. There is some evidence that patients can successfully self-titrate their basal insulin, given proper instruction and an algorithm from their provider. It has been shown that these patients can have similar diabetes control as compared with those solely adjusted by their provider in-office. This approach may also enable patients to become more involved in their diabetes care.
James R. Taylor, PharmD, CDE, is a Clinical Associate Professor in the Department of Pharmacy Practice at the University of Florida in Gainesville.
For more information:
- Holman RR. N Engl J Med. 2009;361:1736-1747.
- Meneghini L. J Fam Pract. 2007;56:19a-29a.
- Nathan DM. Diabetes Care. 2009;32:1-11.