Insulin analogues

Synonyms

Artificial insulin; modern insulins;

First described by

Since expectations were not fully met after the introduction of human insulins in the 1980s (onset of action too late, duration of action too long, etc.), modified insulin analogues were developed in the late 1990s(Hürter 2013).

A distinction is made between fast-acting and slow-acting insulin analogues. Fast-acting analogues came onto the market in 1996 and long-acting analogues in 2000 (Egidi 2019).

Insulin analogs are insulins produced synthetically using bacteria(Escherichia coli) and yeast(Saccharomyces cerevisiae) (Huismann 2005), which do not require any mixing before injection (Herold 2018).

They were developed to better mimic the physiological insulin profile through improved pharmacokinetic properties (Hartman 2008).

Insulin analogues are differentiated between:

• Ultra short-acting:

The insulin aspart could be modified by the addition of niacinamide (vitamin B3) in such a way that the onset of action already starts after 4.9 min (Meißner 2021/ Haak 2018). The duration of action is approximately 3.5 h (Herold 2018).

• Short-acting:

For these, such as insulin-glulisine (Apidra), the onset of action occurs after about 20 - 25 min, and the duration of action is 4 - 5 h (Haak 2018).

• Long-acting:

The onset of action is on average 1 h and the duration of action is usually between 20 - 28 h, with insulin Degludec it is even 42 h (Herold 2018).

Pharmacodynamics

In normal insulin, DNA synthesis occurs exclusively via activation of the insulin receptor. In contrast, signal induction by the IGF-I receptor plays an important role in insulin analogs (Eckhardt 2007).

A mitogenic effect feared as a result has not yet been confirmed (Haak 2018).

• Short-acting insulin analogues:

Here, a variation of the amino acid sequence prevents the subcutaneous formation of hexamers. This causes the more rapid absorption (Herold 2018). Short-acting insulin analogues best mimic the physiological secretion of insulin in the first postprandial phase (Jahn 2020 / Rodbard 2020).

• Long-acting insulin analogues:

By changing the insulin structure, a significant prolongation of the duration of action is achieved, which is usually between 20 - 28 h (Herold 2018).

In the case of the particularly long-acting insulin Degludec, the effect sets in after 0.5 - 1.5 h and even lasts up to 42 h (Meißner 2021).

Indication

Insulin analogues can be used in all forms of insulin therapy for type 1 or type 2 diabetes (Prinz 2012) such as:

• SIT (supplementary insulin therapy)
• intensified insulin therapy (both ICT and insulin pump therapy [Herold 2021])
• basic bolus concept (Alawi 2019)
• conventional insulin therapy (Greten 2005)

Dosage and type of application

Mode of administration:

Insulin analogues can be administered by pen, pump, and closed-loop systems (Jahn 2020).

Insulin analogues are administered s. c. Short-acting insulin analogues such as aspart, glulisine, and lispro are also approved for i.v. administration, but this does not provide any clinical advantage (Danne 2016).

Short-acting insulin analogues should be injected into the abdominal wall (faster absorption) and long-acting ones into the front or outer thigh. For mixed insulins, it is recommended to inject into the abdominal wall in the morning and into the thigh in the evening (Schubert 2009).

Dosage

The daily insulin requirement of a healthy person is 0.67 I. E. / kg / d = approx. 40 I. E. Of this, about 40% is for basal secretion and about 60% for postprandial (Dellas 2018 / Seifert 2018). For more details, see. Insulin

Lowering blood glucose:

To achieve a decrease in blood glucose of 30 - 40 mg / dl (1.6 - 2.2 mmol / l), 1.0 I.U. normal insulin or rapid-acting analog insulin is required (Haak 2018).

Raising blood glucose:

To achieve an elevation of blood glucose by 30 - 40 mg / dl (1.6 - 2.2 mmol / l), 10 g of carbohydrate = 1 KE is required (Haak 2018).

The size of the meal is measured in carbohydrate units = KE, the outdated term is bread unit = BE [Dellas 2018]) (Herold 2021).

A higher dose of insulin may be required, for example, for:

• Blood glucose > 270 mg / dl
• Dehydration
• Infections
• Fever
• Detection of ketone bodies (Haak 2018).

A lower dose of insulin may be needed in cases such as:

• insufficiency of the adrenal cortex
• severe renalinsufficiency
• Liver insufficiency
• physical stress (Haak 2018)

Advantages

• Short-acting insulin analogues:
  • Low risk of nocturnal hypoglycemia (e.g., for glargine P = 0.00003 or detemir P < 0.00001)
  • Low mean incidence of severe hypoglycemia (21.8 per 100 person-years; with normal insulin, 46.1 per 100 person-years [Hartman 2008])
  • less frequent occurrence of postprandial hypoglycemia
  • in most cases it is possible to do without snacks between meals
  • no or short injection-meal interval
  • postprandial injection possible (Herold 2018)

• Long-acting insulin analogues:
  • no strong maximum effect
  • great temporal flexibility of the injection time (especially with insulin glargine) (Meißner 2021)
  • fewer hypoglycemias due to the lack of a maximum effect (compared to, for example, protamine Hagedorn insulin)
  • Less weight gain than with protamine hagedorn insulin [Tibaldi 2014]).
  • Detemir is the only insulin analog to show a weight-maintaining effect (Hartman 2008)

Disadvantages

• Short-acting insulin analogues:
  • Need for exact dosing of basal insulin supply
  • Effect may be too short with slowly absorbed carbohydrates (Herold 2018)

Contraindication

Absolute contraindications:

• Hypoglycemia
• Insulinoma (Flake 2021)

Preparations

Short-acting insulin analogues include:

• Insulin Aspart (NovoRapid) Onset of action after 20 - 25 min, duration of action 4 - 5 h (Haak 2018).
• Faster Aspart onset of action after 4.9 min (Meißner 2021/ Haak 2018), duration of action approx. 3.5 h (Herold 2018)
• Insulin- Glulisin (Apidra) Onset of action after 20 - 25 min, duration of action 4 - 5 h (Haak 2018)
• Insulin- Lispro (Humalog) Onset of action after 20 - 25 min, duration of action 4 - 5 h (Haak 2018).

(Herold 2018)

Long-acting insulin analogues include:

• Insulin Detemir (Levemir) Onset of action after 1 h, duration of action 19 -26 h (Haak 2018).
• Insulin Glargine (biosimilar Abasaglar , Lantus) Glargine U100: onset of action after 1 h, duration of action 20 - 27 h; Glargine U300: onset of action after 1 - 6 h, duration of action 30 - 32 h (Haak 2018) (Haak 2018).

(Herold 2018)

• Insulin Degludec (Tresiba) onset of action after 1 - 2 h, duration of action > 42 h (Haak 2018).

Premixed insulin analogs include:

• 75 / 25 Humalog / Eli Lilly: 75% neutral protamine- lispro, 25% lispro.
• 50 / 50 Humalog / Eli Lilly: 50 % neutral protamine- lispro, 50 % lispro
• 70 / 30 Novolog / Novo Nordisk: 70 % protamine aspart, 30 % aspart (Ferri 2021 / Hartman 2008)

For premixed insulin analogues: onset of action after 20 - 25 min, duration of action 10 - 14 h (Haak 2018).

• Combination insulin Degludec (70) / Aspart (30).

For combination insulin: onset of action after 20 - 25 min, duration of action > 30 h (Haak 2018).

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 groupwith 8.11%.

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

Mean HbA1c 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 improved HbA1c- setting.

Macrovascular complications such as cerebrovascular disease, ischemic heart disease, peripheral vascular disease, which occur in particular 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)

DEGAM and AkdÄ

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 insulins 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 societies 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 cite a 2020 study by Mertes (Successful Treatment with Bedtime Basal Insulin Added to Metformin without Weight Gain or Hypoglycaemia over Three Years) that included 285 type 2 diabetics (Bundesärztekammer 2021).

DDG and DGIM

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, the non-existing need for panning before injection (in contrast to NPH- insulins, where mixing errors can occur due to insufficient panning).

(German Medical Association 2021)

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