Evidence for the use of insulin analogues

In the last two decades, insulin analogues have gained widespread popularity, with most patients in the Western world using short-acting analogues rather than human (regular) insulin, and long-acting analogues driving out NPH insulin. While there are definitely some circumstances in which the insulin analogues may offer a benefit, many patients will do very well with the cheaper conventional insulins. Thus, the decision to start insulin analogues in an individual patient should be taken only when the conventional insulins have been proven inadequate.

Evidence for the use of short-acting insulin analogues

The short-acting insulin analogues are known for their more rapid absorption after subcutaneous injection, resulting in an earlier insulin peak and a shorter duration of action compared to human regular insulin. This is generally thought to translate into three clinical benefits:

  1. the ability to inject the insulin-analogue just before the meal
  2. lower postprandial glucose excursions
  3. a reduced the risk of (nocturnal) hypoglycaemia

As for the first point, it is true that the more rapid onset of action allows for a shorter time-interval between injection and meal. It has been shown that the instruction to inject regular insulin more than 20 minutes before a meal is widely disregarded, and a shorter time interval between injection and meal is appreciated by patients. It should however be noted that many factors influence the pharmacokinetics of insulin absorption. Thus, it was demonstrated that in obese patients (with a thick subcutaneous fat layer) the absorption of s.c. injected insulin and insulin analogues is clearly slowed down, so that earlier injection may still be necessary, and the benefits of the short-acting insulin analogues may not materialize in all of these patients.

As for the second point lower postprandial glucose excursions have indeed been demonstrated in most studies. However, these have generally not translated into improved overall glycaemia, probably because late postprandial and night-time glucose levels tend to be a bit higher in basal-bolus regimens that apply short-acting insulin analogues. In a Cochrane meta-analysis, overall decrease in Hba1c, as a measure of average glycaemia was only about 0.1-0.2% in favour of the short-acting analogues, which is hardly relevant (and in fact was not even signifcant in type 2 diabetes).

As for the third point, while the Cochrane group and an independent Canadian meta-analysis found no evidence for a reduction in hypoglycaemia rates, company meta-analyses such as for insulin lispro, tend to show a slight reduction in overall hypoglycaemia rates of about 10% and also in severe hypoglycaemia rates.

In conclusion, the benefits of the short-acting Figure 1. Clinical benefits of the short-acting insulin analogues compared to regular insulin in type 1 diabetes are limited to a small decrease in HbA1c and no difference in hypoglycaemia.
Figure 1. Clinical benefits of the short-acting insulin analogues compared to regular insulin in type 1 diabetes are limited to a small decrease in HbA1c and no difference in hypoglycaemia.
insulin analogues are limited to a very slight reduction in HbA1c, a possible decrease in hypoglycaemia rates and some improvement in patient convenience.

When used in insulin pumps, the advantages of the short-acting insulin analogues seem to be somewhat larger, but even so the reductions in HbA1c and/or hypoglycaemia rates are modest. This would make these analogues mainly suitable for those already in very tight glycaemic control, who tend to have the higher hypoglycaemia rates. Despite the evidence, however, virtually all patients in the developed world these days use short-acting insulin analogues. Since these insulin-analogues seem to be safe this is not much of a problem from a clinical point of view. The only concern relates to the excess costs of the insulin analogues, but in many countries the price of the short-acting insulin analogues has been reduced to levels close to those of regular human insulin. Where this is not the case, conventional regular insulin remains the first-line drug of choice.

Evidence for the use of long-acting insulin analogues

The Long-acting insulin analogues that were first developed, Insulin detemir and Insulin glargine, were compared to the conventional long-acting NPH insulin. Despite the fact that neither of the newer analogues performed clearly better than the conventional 'gold-standard' NPH insulin, the last long-acting insulin analogue to be developed, Insulin degludec, has only been compared to the other insulin analogues. The long-acting insulin analogues tend to have a longer duration of action, with lower peak insulin levels than NPH insulin, and this is thought to translate into improved night-time and fasting glycaemia with a concomitantly reduced risk of (nocturnal) hypoglycaemia.

As with the short-acting insulin analogues, in clinical practice these benefits have materialized only to a limited extent, with some differences between the different long-acting analogues.

Insulin detemir

Of the three long-acting insulin analogues, Figure 2. Duration of different doses of detemir versus NPH insulin
Figure 2. Duration of different doses of detemir versus NPH insulin
detemir has the shortest duration of action, which is almost similar to the duration of action of NPH insulin at lower doses (figure 2). It is therefore not surprising that in most meta-analyses detemir does not improve HbA1c levels compared to NPH insulin and may in fact be slightly inferior (by about 0.1% = 1mmol/L). On the other hand, detemir is associated with an about 20-30% reduced risk of nocturnal hypoglycaemia and less weight gain (difference about 0,3 kg).

In a Cochrane review of studies comparing insulin detemir to insulin glargine, no relevant differences between the two could be established except for slightly less weight gain with insulin detemir; however, detemir was often used twice daily and insulin doses tended to be higher when using detemir. A direct comparison of once daily detemir and once daily glargine in type 2 diabetes found glargine to result in significantly better HbA1c (by 0.4%) but somewhat higher risk of hypoglycaemia (possibly as a result of lower overall glycaemia).

Insulin glargine

Despite its huge popularity, the objective benefits of glargine compared to NPH insulin are limited, with no or a very slight (0,1%) difference in HbA1c and a 15-30% reduction in hypoglycaemia rates. As a basal insulin in type 2 diabetes it probably performs better than detemir (see above); the relative merits of degludec compared to glargine are not yet fully established.

Insulin degludec

The recently introduced insulin degludec has been associated with about 15-20% lower hypoglycaemia rates compared to insulin glargine in type 2 DM. In type 1 diabetes, there was only a difference in nocturnal hypoglycaemia but not in overall hypoglycaemia, which may reflect different injection times and absorption kinetics. HbAc levels achieved seem generally the same for degludec and glargine. Unfortunately, independent meta-analyses of the effects of deglude compared to other insulin analogues are still lacking.

Combining short- and long-acting insulin analogues

Two trials have compared 'all-conventional', i.e. NPH insulin plus 3 or more injections of human insulin, with 'all-analogue' regimens (either twice-daily detemir plus thre injections of insulin aspart, or once-daily glargine plus three injections of insulin lispro) in type 1 diabetes. In both studies, the 'all-analogue' regimen performed better, with a greater reduction in HbA1c (by about 0,3-0,5% = 3-5 mmol/mol) and a concomitant 20-30% decrease in hypoglycaemia. As with most insulin trials, however, these studies were not double-blind so some study effects due to increased attention in the newer regimen cannot be excluded.

A cautionary note

The overall benefits of insulin analogues have been somewhat disappointing and are limited to slight differences in hypoglycaemia rates. However, when making clinical decisions based on perceived differences in hypoglycaemia risk, one should always take into account the baseline hypoglycaemia risk. In basal only regimens in type 2 diabetes, absolute hypoglycaemia risks are low so the introduction of a long-acting insulin analogue (instead of NPH insulin) should only be considered in those with well-documented frequent hypoglycaemia. In those with type 1 diabetes or long-standing type 2 diabetes who use basal-bolus regimens, hypoglycaemia risks tend to be higher so the cost-benefit ratio of using the more expensive analogues improves; but even in these patients, quite a few will do equally well using the conventional insulins. The choice of insulin is only a very small part of getting a patient into good glycemic control, and as Elliot Joslin already stated in 1946: “Eventually, all physicians and patients hope for an insulin which will combine more of the good effects of both crystalline and zinc insulin, but one must never expect that any insulin will have brains”.

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