Named after its inventor, Hans Christian Hagedorn, NPH (neutral protamine Hagedorn) insulin has been the long-acting insulin of choice for almost 80 years and only in the last few years has lost some of its popularity to the newer long-acting insulin analogues. When first used in 1936 it was considered an excellent solution to reduce the burden of multiple injections associated with the use of regular insulin. Having a duration of action of about 14-20 hours, it is still frequently used as the basal insulin in multiple injection therapy, or as a once-daily basal insulin in those with type 2 diabetes failing on oral agents.
Discovery of NPH insulin
Insulin is an acidic molecule with an iso-electric point around pH=5.4, and as such it is ionized at the neutral pH of the body and thus water soluble. This allows for fairly rapid diffusion of the insulin from the injection site. Hans Christian Hagedorn conceived the idea of producing an insulin compound that was less soluble by mixing it with a basic protein, so that the resulting semi-crystalline mixture had an iso-electric point closer to the neutral pH. As basic protein he used a protamine derived from the sperm of the rainbow trout (Oncorhynchus mykiss).
Figure 1. The rainbow troutOriginally, he was unsuccessful, but once the pH during the mixing reaction was adjusted to neutral pH, the mixture precipitated to form a 1:1 insulin-protamine suspension. Subsequently, it was found that the addition of small amounts of zinc led to a stable compound with a prolonged duration of action.
Practical use of NPH insulin
The NPH insulin suspension is only registered for s.c. use.
After s.c. injection, NPH insulin has a relatively slow onset of action, with a peak action after about 4-8 hours, and a duration of action of about 14-20 hours.
While the insulin and protamine are present in equal amounts in the NPH suspension, the suspension itself has a tendency to settle in the vial/penfill, so that it may not be equally distributed throughout the injection fluid. Therefore, it is recommended to roll or lightly shake the insulin suspension prior to use, to ensure that the right amount of insulin is given. M-Cresol and phenol are added as preservatives, and may sometimes be responsible for presumed allergies to the product.
Because of its notable peak action, NPH insulin does not quite meet the qualifications of an ideal basal insulin. When given at bedtime or in the evening, it will sometimes lead to nocturnal hypoglycaemia. Also, the waning of the insulin action after 14-20 hours may sometimes lead to pre-dinner hyperglycaemia the following day. This was one of the main reasons the long-acting insulin analogues were developed and these may indeed be associated with slightly less hypoglycemic episodes. But having said so, many patients will have satisfactory results with the cheaper and more easily available NPH insulin.
NPH insulin is used in many insulin regimens. Its most common uses are as:
- the basal component in basal-bolus therapy in either type 1 or type 2 diabetes. As such it is given either once or twice daily (although the evidence for twice daily use is unconvincing)
- the once (or twice) daily basal insulin in those with type 2 diabetes who initiate insulin therapy after failing oral agents. It is then usually combined with either metformin alone, or metformin + a sulfonylureum derivative.
NPH is also the long-acting component of the classical mix-insulins. These consist of varying percentages of regular insulin and NPH insulin, most frequently 30/70.