Since 1922, when insulin was first developed, opinions about what constitutes the best insulin regimen have varied. The first regimens consisted of multiple (up to 4 times daily) injections of the short-acting regular animal insulin. Since these injections were painful, a mode of prolonging insulin action was sought and found in NPH-insulin and Zinc-insulins. These allowed people to get by on 1 or 2 injections daily. When the notion took hold that complications result from (postprandial)hyperglycemia, mix-insulins (that contain both a short-acting and a long-acting component) became popular, shortly afterwards followed by basal-bolus therapy consisting of 1 (or 2) daily injections of long-acting insulin in combination with short-acting insulin injections with each meal. The same principle was applied in the insulin pumps, where the basal component is given in the form of a continuous infusion. Lately, once daily basal insulin has become popular for those with type 2 diabetes starting on insulin. While many combinations are used at an individual level, these days the common insulin regimens are once daily basal insulin, twice daily insulin mix, and basal-bolus therapy with 1 basal and 3 meal injections (see figure).
Once daily basal insulin
Many patients with type 2 diabetes will eventually need insulin to maintain normoglycaemia. However, at the time of so-called 'secondary failure', when oral agents alone do not suffice anymore, patients still have some beta-cell reserve and are still able to produce some insulin themselves. The once-daily basal insulin regimen capitalizes on this: it provides the basal insulinemia, necessary to keep hepatic glucose production suppressed, with a single injection of long-acting insulin and relies on the patient's own insulin for meal-coverage. Traditionally, the long-acting insulin is given in the evening/at bedtime because the duration of NPH action does not last 24 hours and injecting at bedtime ensures coverage of the night and most of the daytime. However, with the longer acting insulin analogues it is also possible to give the injection in the morning.
This regimen has two main benefits. Since many patients are reluctant to start on insulin, starting with one injection is generally better accepted than starting with 2 or 4 injections. The evening dose can easily be titrated by increasing the dose every 2-3 days so long as fasting glucose remains above the target (usually around 6 mmol/l). Using a single dose of basal insulin in those with type 2 diabetes initiating insulin will result in good glycemic control in about 70% of patients, with a low percentage (about 30-40%) of patients experiencing a few (about 6) episodes of mild hypoglycaemia per year.
While there are some advantages to using long-acting insulin analogues such as glargine (notably a slightly lower risk of hypoglycaemia), most patients will do well on the cheaper NPH-insulin, which therefore remains the first choice for this regimen.
As beta-cell failure in type 2 diabetes progresses, glycemic control will eventually deteriorate and necessitate the introduction of meal-related insulin. This can be done by switching to a twice daily mix-insulin regimen, or by switching to basal-bolus therapy. The latter can also be done in a stepwise fashion, introducing first one injection of short-acting insulin with the main meal, then the second, and then the third meal-injection.
The mix-insulins are a fixed combination of a short-acting insulin and a long-acting insulin. Nowadays, these are all 30/70 mixtures, meaning that 30% of the insulin is short-acting, and 70% is long-acting. Historically, there have also been 10/90, 20/80, 40/60 and 50/50 mixtures, but since the 30/70 mixtures turned out to best meet daily requirements these other mixtures are now almost obsolete.
Using mix-insulin twice daily before breakfast and dinner has the advantage that it provides both 24-hour basal insulinemia, and meal-related insulin substitution for two meals. The regimen can be titrated fairly easily (increasing the dinner dose based on pre-breakfast glucose values, and the breakfast dose on pre-dinner values) and because it takes only 2 injections it is a relatively well-accepted mode of therapy. However, the fixed combination has the disadvantage that it is not possible to adjust the meal-dose (e.g. prior to exercise, or in the context of a missed meal) without affecting basal insulinemia, which makes it less suitable for those with more flexible lifestyles.
While the conventional (regular insulin/NPH insulin) mixtures are being replaced globally by modern (short-acting analogue/protamine analogue) mixtures, this is mainly the result of the marketing strategies of the insulin manufacturers. Objective benefits of the modern mixtures over the conventional mixtures have not convincingly been demonstrated, which is not so surprising when one considers that the short-acting and long-acting components will interact in the vial, thereby lessening the rapidity of action of the short-acting analogue.
Also known as 'intensive insulin therapy' or multiple-injection therapy (MIT), basal-bolus therapy aims to mimic the physiologic situation of a low fasting basal insulinemia with steep increases in insulin levels with the meals, in an attempt to attain 'perfect' glycemic control. The basal insulinemia is provided by a long-acting insulin, and the meal-surges are provided by bolus-injections of short-acting insulin with each meal. While this approach indeed offers the best chances of controlling glycaemia and is well-suited for those with flexible lifestyles, it requires frequent glucose-control and active self-adjustment of (meal) insulin dosages which may make it to laborious or complex for some patients. It is the mode of choice for most patients with type 1 diabetes, and those with long-standing type 2 diabetes may eventually require basal-bolus therapy as well.
Using short-acting and/or long-acting insulin-analogues in basal-bolus therapy has some advantages, most notably a reduced risk of hypoglycaemia. Hence, most patients will nowadays use both a long-acting insulin analogue and 3 injections of short-acting, even though some patients can also manage good control with NPH insulin and 3 injections of regular insulin.
Which regimen for which patient?
Clear and undisputed evidence which regimen serves which patient best is lacking, and trials such as the 4T-study, while demonstrating some differences between regimens, serve mainly to remind us that the objective differences between regimens are not so important as to overrule individual practical considerations. However, some general recommendations can be made. Those without residual beta-cell function (i.e. type 1 diabetes, long-standing type 2 diabetes) will usually not be able to safely regulate their diabetes with a single dose of long-acting insulin; a basal-bolus regimen is usually the preferred treatment although practical considerations may lead to choosing a twice-daily mix-insulin (e.g. in those dependent on others for their care such as children or nursing home residents) Those with type 2 diabetes starting insulin will usually begin with a once daily basal insulin in the evening/at bedtime and with progressive beta-cell failure progress to more intensive regimens.
^ Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009;1736-47.