Nph insulin

Synonyms

Isophane insulin; Berlin insulin H basal; neutral protamine Hagedorn; isophane insulin neutral protamine Hagedorn;

Initial describer

NPH- Insulin (Neutral- Protamin Hagedorn) was introduced by Hans Christian Hagedorn (Saleem 2021) in 1946 (Hagedorn 1946). In Germany, it was used as an almost exclusive long-acting insulin until the end of the 1990s (Berger 2013). At that time, the modified insulin analogues were developed (Hürter 2013).

NPH insulins are among the intermediate-acting insulins (Kasper 2015). They are on the WHO list of essential medicines (Saleem 2021).

NPH was the only basal insulin for a long time after its discovery. It was used together with metformin and / or sulfonylureas for the standard treatment of diabetes mellitus. Only after the development of basal insulin analogues were other insulins available for diabetics (Saleem 2021).

Currently, NPH continues to be the most commonly used insulin for diabetes mellitus (Saleem 2021), as the cost-benefit of insulin analogues is still controversial (Aschner 2020).

NPH- insulins can be mixed with other insulins such as:

• short-acting normal insulin (the only exception being zinc insulins [Herold 2022]). Short-acting normal insulin mimics physiological insulin secretion during meals (Kasper 2015).
• Rapid-acting insulin analogues (Robinson 2006):

It should be noted that when mixing with insulin, glulisine fresh in a syringe should be mixed exclusively with NPH insulin and should be injected immediately thereafter (Weihrauch 2020).

Pharmacodynamics

NPH- Insulin is an insoluble, intermediate-acting suspension (Saleem 2021), which must be brought into mixture before injection. This is done by rolling between the palms of the hands or swiveling the pen 180 degrees (Mehnert 2003).

NPH contains protamine and insulin in isophanic amounts. The pH value is neutral. This is ensured by adding a phosphate buffer (Berger 2001).

The peptide protamine was originally obtained from fish sperm; it reacts strongly alkaline. Insulin, on the other hand, reacts acidically and is bound to protamine. The delay effect of insulin is due to the fact that in subcutaneous adipose tissue the insulin molecules dissociate from the protamine molecule (Mehnert 2003).

The tasks of NPH insulin are manifold:

- It simulates the physiological basal insulin action.

- It helps increase cellular uptake of glucose in the liver, skeletal muscle, and adipose tissue.

- It also stimulates the liver for glucogen synthesis, lipoprotein synthesis and fatty acid metabolism.

- In skeletal muscle, it promotes both protein and glycogen synthesis.

- In adipose tissue, it regulates lipolysis by inhibiting triglyceride hydrolysis and supports triglyceride synthesis.

- At the cellular level, it ensures cell membrane permeability to ions such as potassium, magnesium and phosphorus and additionally increases their uptake into the cell (Saleem 2021).

The onset of action occurs after 1 - 2 h, and the duration of action is about 14 h (Haak 2018).

Peak effect is reached after 4 - 8 h and in plasma after 6 - 10 h (Saleem 2021).

- Mixed insulin e.g. 70 NPH and 30 normal insulin: onset of action after 30 - 60 min, duration of action 14 h (Berger 2001).

Metabolism occurs mainly in the liver, to a lesser extent in kidneys and muscles. The metabolites are excreted in the urine (Saleem 2021).

Mixing of insulins - the so-called isophany (Mehnert 2003) - can lead to a change in the insulin absorption profile: absorption is shortened, for example, when mixing lispro with NPH (Kasper 2015).

Indication

NPH is approved for both children and adults with type 1 and type 2 diabetes (Saleem 2021).

Possible uses:

• Conventional therapy.

Used in conventional therapy (CT) is usually a mixed insulin, often consisting of 70-75% intermediate insulin (NPH) and 25-30% normal insulin (Greten 2005).

• Gestational Diabetes (Saleem 2021).

Dosage and route of administration

NPH insulin is administered subcutaneously. It is not approved for i.m. or i.v. administration. When injected into the abdomen, absorption is faster than when injected into the arms or legs (Saleem 2021).

The basal insulin supply accounts for approximately 40-50% of the total daily insulin dose.

According to the American Diabetes Association, a subcutaneous NPH dose of 0.4 - 1.0 I E / kg / d is recommended for therapy in type 1 diabetes. However, in acute diseases and during puberty, the requirement is higher.

In type 2 diabetes, the requirement for NPH insulin is 0.1 - 0.2 I E / kg / d s. c., whereby the treatment must be individually adjusted and the dose titrated accordingly over days to weeks in the case of readjustment (Saleem 2021).

Because the NPH- action profile does not cover 24 h (Saleem 2021), basal insulin requirements can be achieved in most cases by injecting an NPH- delaying insulin at least twice (Herold 2021).

Adverse effects

• Hypoglycemia:

Because NPH has a significant peak, hypoglycemia occurs more frequently (Kasper 2015).

Patients with renal or hepatic dysfunction are particularly at risk for this (Saleem 2021).

In type 1 diabetics, the number of hypoglycemias can be reduced by using insulin detemir instead of NPH insulin. In studies, the number of hypoglycemic events per person-year with detemir was 37.1 and with NPH-insulin 48.2, and the number of nocturnal hypoglycemic events was 4.0 and 9.2, respectively (Haak 2018). Nocturnal hypoglycemias occur with NPH, particularly around midnight (Saleem 2021).

Insulin analogues were compared with other insulin preparations in a large study:

- 1st insulin aspart / insulin detemir with NPH insulin / regular insulin:

The mean HbA1c in the aspart/detemir group was lower at 7.88% compared to 8.11% in the NPH/regular-insulin group (Hartman 2008).

Also, in older type 2 diabetics 65 years and older, a 12+ year study of more than 500,000 participants receiving the insulins glargine, detemir, and NPH showed that long-acting insulin analogs demonstrated a lower risk of hypoglycemia , and the number of emergency department visits and inpatient stays were nearly 30% lower than when NPH insulin was administered.

However, this protective effect was age-dependent and most pronounced between 69-87 years of age. However, this relationship was not found with concomitant use of prandial insulin (Bradley 2021).

Another reason for frequent hypoglycemia is certainly the fact that NPH insulins must be swished at least 20 times before use in order to achieve uniform mixing (Saleem 2021). Studies have shown that only about 10% of diabetics swivel sufficiently, which means that the dose of insulin administered to them is between 10 and 200% of the prescribed dose. The risk of hypoglycemia is correspondingly high (Herold 2022).

• Fasting hyperglycemia

On the one hand, fasting hyperglycemia can occur as part of a dawn phenomenon . On the other hand, hyperglycemia may be caused by insufficient duration of NPH action. In the latter case, evening NPH should be administered just before bedtime (Saleem 2021).

• Weight gain

NPH- insulins are more likely to cause weight gain (Fournier 2014).

• Allergic reactions:

Both Eapen et al (2000) and Hasselmann et al (2013) reported 3 cases in which allergic reactions to NPH- insulin or other human insulins occurred. Symptoms improved after switching to insulin lispro (Kaiserman 2017).

Other adverse effects may include:

• peripheral edema
• Lipodystrophy (May manifest as skin at rophy or skin hypertrophy ).
• hypokalemia (Saleem 2021)

Contraindication

• allergic reactions to NPH or additives such as zinc, metal cresol, protamine
• repeated severe hypoglycemia (Saleem 2021)

Preparations

NPH insulins include:

- Berlinsulin H Basal

- protaphane

- Insuman Basal

- Huminsulin Basal (Alawi 2019)

NPH is not classified as an ideal basal insulin because it is

• after s. c. has large fluctuations in effect and absorption after injection
• can cause hypokalemia (regular monitoring of electrolytes required)
• frequent BG checks are required in the treatment of children, as insulin requirements change considerably, especially during growth phases (Saleem 2021).

Recent clinical studies have shown that modern basal insulin analogues, such as insulin glargine and insulin detemir, have a lower variability of fasting blood glucose and, most importantly, a lower risk of hypoglycemia (Saleem 2021).

The cost of therapy for insulin detemir, for example, is EUR 1.91 for a dose of 40 IU. This is almost twice as high as for NPH insulin, for example (Schwabe 2005).

The DEGAM (German Society for General and Family Medicine) and the AkdÄ (Drug Commission of the German Medical Association) do not see any advantage over NPH insulin with regard to long-acting insulin analogues, since long-term consequences of NPH insulin can be better assessed. In addition, the nocturnal course of action of NPH insulins would correspond most closely to the physiological effect of insulin. The above-mentioned companies are of the opinion that the risk of hypoglycemia with NPH insulins is overestimated by the strict target values and that therapy with NPH insulins leads neither to nocturnal hypoglycemia nor to weight gain. They refer to a study by Mertes (Successful Treatment with Bedtime Basal Insulin Added to Metformin without Weight Gain or Hypoglycaemia over Three Years) from 2020, which included 285 type 2 diabetics (Bundesärztekammer 2021).

The DDG (German Diabetes Society) and the DGIM (German Society of Internal Medicine), on the other hand, prefer long-acting insulin analogues over NPH insulins because of the low rate of nocturnal hypoglycemia, the possibility of a flexible choice of injection with regard to the time of day, and the absence of the need for panning before injection (in contrast to NPH insulins, where mixing errors can occur due to insufficient panning).

(German Medical Association 2021)

Insulin analogues are - in contrast to comparable human insulin - on average 35-60% more expensive (Schwabe 2008).

In three large studies, insulin analogues were compared with other insulin preparations:

- 1. aspart / insulin detemir with NPH insulin / regular insulin:

The mean HbA1c in the aspart / detemir group was 7.88%, lower than in the NPH / Regular- insulin group at 8.11%.

- 2. glargine plus lispro with NPH plus unmodified human insulin:

The mean HbA1c- value was 7.5% in the glargine plus lispro group and 8.0% in the NPH plus unmodified human insulin group.

- 3. glargine/lispro with NPH/regular insulin:

In the glargine- lispro- group, the mean HbA1c- value was 8.7% and in the NPH / regular insulin- group it was 9.1%.

(Hartman 2008)

Microvascular complications of diabetes such as nephropathy, neuropathy, retinopathy could be reduced by an improved HbA1c- setting.

Macrovascular complications such as cerebrovascular disease, ischemic heart disease, peripheral vascular disease, which occur particularly in type 2 diabetics due to postprandial hyperglycemia, are also found less frequently under treatment with insulin analogues lispro and glargine - compared with NPH / human insulin (15% lower postprandial BG values).

(Hartman 2008)

In pregnant type 2 diabetics, there were no differences in neonatal morbidity and maternal complications with NPH or basal insulin therapy (Bartal 2020).

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