Eric L. Johnson, MD Department of Family and Community Medicine, University of North Dakota School of Medicine and Health Sciences; Altru Diabetes Center, Grand Forks, ND ejohnson@medicine.nodak.edu
Dr. Johnson is on the speakers’ bureau of Novo Nordisk and Medtronic Minimed. He received writing assistance for this article from the Med Ed Group, which was funded by Novo Nordisk.
The Journal of Family Practice no longer accepts articles whose authors have received writing assistance from commercially sponsored third parties. This article was accepted prior to implementation of this policy.
Turning to insulin earlier. Insulin is most effective for lowering HbA1c and delaying subsequent complications related to diabetes; however, there is often reluctance to using it early in diabetes management. Consequently, by the time insulin therapy is started, many patients will have had unacceptable glycemic levels for 10 years or more and may already be developing complications.27 And, as noted, the HbA1c level is an average measurement that does not detect glycemic variability. Continuous glucose monitoring will likely lead to more responsive adjustments in treatment regimens and to improved quality of care for patients with T2DM.
Insulin has many beneficial effects
Insulin exerts an anti-inflammatory effect by reducing the increase in C-reactive protein and serum amyloid A.30 It also partially restores insulin-stimulated endothelial function,31 facilitates vasodilation by increasing nitric oxide production,32 and improves fibrinolytic profiles.33 Early initiation of insulin therapy can increase peripheral insulin sensitivity and preserve beta cell function.34-36
When oral agents have failed, insulin can significantly improve patients’ beta cell function,34,35,37 and short periods of insulin therapy in patients newly diagnosed with T2DM may even set the foundation for better long-term control.38,39
But not all insulin is alike Ideally, insulin therapy should mimic physiologic insulin secretion. However, conventional human insulin products fail to do so because of their suboptimal pharmacodynamic profiles. With recombinant DNA technology, molecular modifications of the human insulin molecule have overcome some of the limitations of conventional human insulin products.
Unfortunately, many practitioners still hold insulin in reserve until combination therapy with oral agents has failed, possibly resulting in years of suboptimal glycemic control. Newer strategies recommend earlier initiation of insulin—ie, once diet and exercise fail, or when treatment with 1 oral agent fails. The development of insulin analogs is a significant milestone on the road to achieving improved outcomes for patients with T2DM.
Rapid-acting agents Compared with regular human insulin, newer rapid-acting insulin analogs may improve glycemic control when used at mealtimes. However, due to their shorter half-lives, these insulin analogs require augmentation with basal insulin to control hyperglycemia between meals and during the night.
Insulin lispro was the first commercially available rapid-acting insulin analog, introduced in 1996. This agent differs from human insulin by an inversion of amino acid residues in positions 28 and 29 of the insulin B-chain. Inversion prevents the formation of hexamers and dimers that tend to diffuse more slowly, thereby facilitating a rapid uptake of the insulin analog into blood and tissues.40,41 The second such agent, marketed in 2000, was insulin aspart, in which aspartic acid replaces proline at position 28 of the B-chain of human insulin.41,42 The most recent rapid-acting analog is insulin glulisine, in which lysine replaces asparagine near the N-terminus of the B-chain, and glutamic acid replaces lysine near the C-terminus of human insulin.
The molecular changes made in creating these analogs allows them to dissociate quickly into monomers that are absorbed rapidly and achieve faster peak levels compared with regular human insulin.41,42 These changes do not, however, interfere with the analogs’ ability to bind to the insulin receptor.43,44
Dosing considerations. Absorption of regular human insulin is not sufficiently rapid at mealtimes to control prandial glucose levels.45 Therefore, it is essential to give regular insulin 30 to 60 minutes before meals. For patients who have erratic daily schedules, adhering to this sort of routine can be difficult. But even if scheduling is not a problem, the prolonged duration of action of human insulin can predispose patients to hypoglycemia. Moreover, absorption of regular insulin can vary dramatically from day to day.46,47
The insulin analogs correct the pharmacokinetic and pharmacodynamic deficiencies of regular insulin, producing plasma profiles that more closely simulate normal, physiologic meal-stimulated insulin release.48-50 The 3 rapid-acting agents (aspart, glulisine, lispro) have very similar onset and duration of action, with peak effect occurring close to injection time (TABLE 2 and FIGURE 2).48-50
FAST TRACK
Rapid-acting insulin analogs can be taken closer to mealtime, likely giving patients tighter postprandial glucose control and reducing glycemic excursions.
Advantages of rapid-acting agents. These agents can be administered closer to meals, giving patients more flexibility and likely tighter postprandial glucose control, with reductions in glycemic excursions. Another advantage is the ability to better match insulin dose to anticipated carbohydrate in-take, affording better postprandial control.51-53 Rapid-acting analogs also result in fewer episodes of hypoglycemia. In a meta-analysis of 2576 patients, hypoglycemic events occurred 25% less often with insulin lispro compared with regular human insulin in patients with type 1 diabetes mellitus (T1DM).52 In clinical trials, insulin aspart and insulin glulisine have also caused fewer hypoglycemic events compared with regular human insulin.51-53
