Starting and Advancing Insulin for Type 2 Diabetes: Algorithms and Individualized Methods Are Both Necessary

Abstract

Injected insulin is the best-tested and most powerful treatment for hyperglycemia. Clinical trials show that it can limit microvascular and, perhaps, cardiovascular complications of diabetes. Even so, in clinical practice the use of insulin for type 2 diabetes continues to be delayed, allowing hyperglycemia to persist on oral therapy, and once started is often disappointingly ineffective. Failure to begin or optimize insulin treatment is often attributed to the patient’s fear and incapacity, but success in studies and in specialized diabetes centers argues that other barriers are more important. Attention is increasingly focused on developing suitable algorithms, i.e. standardized protocols for starting and adjusting insulin, to address this problem. For example, continuing oral therapies while starting insulin can improve the results of simple insulin regimens such as a single daily injection of longer-acting (basal) insulin (1). In addition, systematic titration of insulin dosage, seeking a defined, self-measured glucose target, is gaining acceptance. These concepts came together in the Treat-to-Target Trial, which tested the full ability of initiation and systematic titration of neutral protamine Hagedorn (NPH) or glargine insulin, taken at bedtime and with continuation of prior oral antihyperglycemic agents, to achieve the evidence-based 7.0% A1c target (2). Of the 756 patients studied, 58% reached this target (from a mean baseline of 8.6%) by adding either NPH or glargine. This level of success has since been matched in other “treat-to-target” studies, using similar designs and titration schemes, with NPH, glargine, detemir, and premixed insulins (3–6). However, questions remain. Can prandial or premixed insulins be used just as successfully as basal insulin for initial therapy? Can the treat-to-target method be applied as effectively in longterm clinical practice as in trials? What should be done when any initial insulin regimen fails to reach the A1c target? An ambitious new trial directly addressed these questions (7). It is 4T (TreatTo-Target in Type 2 diabetes), sponsored by NovoNordisk but, laudably, conducted and analyzed by the investigators at Oxford University. The 708 patients enrolled were slightly older and less obese than those in the original Treat-to-Target Trial but had similar duration of diabetes, prior oral therapies, and mean baseline A1c. They were randomized to three treatment methods: once or twice-daily detemir, twice-daily premixed 30:70 aspart/ protamine-aspart, or aspart before each meal. Each arm had a specific glucose testing schedule and a computerized algorithm for adjusting dosage based on the results of these tests. In the basal insulin arm, detemir was given only in the evening unless high glucose values persisted in the late afternoon, in which case a second daily injection was to be added each morning. The primary endpoint of the first phase of the trial was the A1c level at 1-yr treatment, after which a 2-yr phase of further intensification of treatment for each arm will follow. The 1-yr results confirmed many implications of the earlier studies. All three regimens improved glycemic control significantly, and a low 1-yr dropout rate ( 6%) indicated good acceptance of insulin therapy. Severe hypoglycemia was uncommon, and few serious adverse events occurred. However, hypoglycemia was more frequent with the premixed and prandial regimens than with basal insulin. Similarly, the mean weight gain with premixed and prandial insulins (4.7 and 5.7 kg, respectively) was much greater than with basal insulin (1.9 kg). Referring to these findings, an accompanying editorial (8) concluded that “prandial and biphasic insulin formulations are suboptimal choices for insulin initiation” and that “the best approach is to continue metformin and add a basal insulin,” as currently advised by American Diabetes Association/European Association for the Study of Diabetes consensus guidelines. Unfortunately, the results of 4T shed no light on whether continuing a sulfonylurea ( 90% of the participants did so) contributed to or limited either glycemic control or hypoglycemia in any of the arms. Other results were more surprising and, thus, informative. First, all the regimens failed to achieve mean glycemic control at