Analogs of Insulin

OCTOBER 30, 2021

Native or regular insulin molecules self-associate as hexamers in an aqueous solution at a neutral PH and this aggregation slows absorption following subcutaneous injection. The onset of action is slow 30-60 minutes, long duration of the peak of 2-4 hours so it can cause postprandial hyperglycemia and late hypoglycemia. There is a mismatch between the need and availability of insulin and does not mimic physiologic bolus secretion of insulin.


Limitations of Regular Insulin

  • Inconvenience: has to be administered 30-60 minutes before a meal.
  • Late postprandial hypoglycemia (4-6 hours after a meal)
  • The dose can not be adjusted according to the size of a meal.
  • Time of onset, peak, and duration are dose-dependent.
  • Absorption varies with the dose, site of injection, and exercise. The variability of absorption is 25%.

Action Profile of Standard Insulin

Rapid Acting
4,8,12 U
10-20 min30-90 min2-3 hrs
Short Acting
Regular (Humulin R)
30-60 min2-4 hrs6-8 hrs
Velosulin (for use in
insulin pump
30-60 min1-2 hrs2-3 hrs
Intermediate Acting
(NPH; Humulin N)
1-2 hrs4-10 hrs10-16 hrs
Novolin N90 min4-12 hrsup to 24 hrs
Zinc insulin
2-4 hrs4-12 hrs12-20 hrs
Extended zinc
6-10 hrs10-16 hrs18-24 hrs
Humulin 70/30
15-30 minvaries18-24 hrs
Humulin 50/5015-30 minvaries18-24 hrs
Novolin 70/3015-30 minvariesup to 24 hrs

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Action Profile of Analogs of Insulin

Ultra-rapid acting
Fast aspart analog
8-15 min30 -90 min3-5 hrs
Rapid Acting
Aspart (Novolog
or Novorapid)
5-15 min30-90 min3-4 hrs
Glulisine (Apidra)15-30 min30-90 min2-4 hrs
Lispro (Humalog)5-15 min30-90 min3-4 hrs
Lispro U-20010-30 min30 min-1 hr8-10 hrs
Long Acting
Detemir (Levemir)
1-4hrsNone12-20 hrs
Glargine (Lantus)1-4 hrsNone20-24hrs
Glargine ( Toujeo)
2-6 hrsNoneup to 36 hrs
Ultra-long Acting
1-4 hrsNone up to 42 hrs
30-60 minNoneup to 42 hrs
Novolog Mix 70/30
10-20 mindual14-24 hr
Humalog Mix75/2510-15 mindual18-26 hrs
Humalog Mix50/5015-30 mindual18-26 hrs
(70% Degludec/30% Aspart)
10-20 min1 hrup to 24 hrs

The time course of action of any insulin may vary in different individuals or at different times, in the same individual. Because of these variations, the time period indicated should be considered as a general guideline only

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The onset of action, peak, and duration of action of different types of insulin

Limitations of NPH Insulin

  • Does not mimic physiological basal insulin secretion.
  • Peak action 5-7 hours after administration so increases the risk of hypoglycemia.
  • The duration of action (4-12 hours) is not long enough to cover the whole day.
  • Action Profile depends on the dose.
  • Variability of absorption with the dose, site of injection, and exercise. Small doses have lower, earlier peaks and a shorter duration of action.
  • Highly unpredictably action profile

There are six analogs of Insulin. Six of them are rapid- acting and six are long-acting analogs. insulin analogs are designed to overcome the limitations of conventional insulins. Different analogs are created by altering the sequence of amino acids of regular insulin molecules to modify their absorption and pharmacokinetics profile.

Rapid Acting Analogs

There are three rapid-acting insulin analogs ( insulin lispro, Aspart, and Glulisine). They have similar time-action profiles. They rapidly absorb from the injection site and start acting within 15 minutes. They can be taken before, during, or even after the meal. They have a lower rate of hypoglycemia and improved A1c levels compared to regular insulin.

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Insulin lispro (Humalog)

Insulin lispro is the first commercially available analog. In insulin lispro amino acids at positions 28 and 29, lysines and proline are reversed in the C- terminus end of the beta chain. A U200 concentration is available in a disposable pre-filled pen.

Insulin Aspart (Novolog)

Insulin Aspart is formed by the replacement of proline at B 28 with aspartic acid which reduces self-association.

Insulin glulisine (Apidra)

Insulin glulisine (Apidra) is formed when glutamic acid replaces lysine at B29 and lysine replaces asparagine at B3

Long Acting Analogs

Insulin glargine, detemir, and degludec are long-acting Analogs. In insulin glargine, two arginine residues are added at positions B31 and 32 of the beta chain, and asparagine amino acid in position A21 is replaced with glycine. Insulin glargine is a clear solution with a pH of 4.0 which stabilizes the insulin hexamers. When injected into neutral PH of subcutaneous space, aggregation occurs, resulting in prolonged, predictable absorption from the injection site. Insulin glargine has a sustained peakless absorption profile and provides more predictable 24 hours insulin coverage than NPH insulin, and it also has a lower risk of hypoglycemia particularly overnight compared to NPH insulin. Suitable for once-daily dosing.


Insulin Detemir

In this insulin, the terminal threonine amino acid at the B30 position is removed and myristic acid (a C -14 fatty acid chain) is attached to B29 lysine. These modifications prolong the self-aggregation in the subcutaneous tissue and reversible albumin binding. Binding to plasma proteins causes gradual release so it has a smoother action profile and causes less hypoglycemia than NPH insulin. Its duration of action is 17 hours and injected once or twice daily.

Insulin Degludec

has modified insulin with threonine amino acid at position B30 is removed and lysine at position B29 is conjugated to hexadecanoic acid via a gamma-L-glutamyl spacer. Degludec which is active at physiologic PH forms multihexamers after injections. It has less severe hypoglycemia than glargine. The half-life of degludec is 25 hours. It is given once or twice daily. It is available in two concentrations U100 and U 200and dispensed in a pre-filled disposable pen.

Premixed formulations

A stable combination of short-acting and long-acting insulin provides convenience by reducing the number of daily injections.

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Advantages of Analogs of Insulin

  • Rapid-acting insulin analogs have an onset of action of 10-20 minutes, a peak of 1-2 hours, and a short duration of action. So have better control of postprandial blood glucose levels and decrease the risk of late hypoglycemia.
  • Greater flexibility. Can be taken before, during, or even after a meal.
  • The dose can be adjusted with the size of the meal.
  • More predictable action. Onset, peak, and duration of action are independent of the site of injection, dose, and variability of absorption is 5 %.
  • Improved A1c levels.
  • Lesser risk of hypoglycemia.
  • Better control of glucose during fasting.
  • Premixed formulations have a lower risk of hypoglycemia than premixed human insulins
  • Less weight gain.

Disadvantages of Insulin Analogs

  • Carcinogenicity: Recently published studies investigating a possible relationship between insulin analogs, in particular, glargine is under review. Glargine is theoretically more likely to cause cancer because of its high affinity six to sevenfold for insulin-like growth factor 1 (IGF-1) receptor. The clinical significance of this is unclear. FDA considered it as a black triangle drug.
  • Cost: More expensive than conventional insulin.

Analogs are preferred in

  • Type-1 diabetic patients
  • A person with an uncertain lifestyle, quantity of meals, and timings of meals.
  • Patients having highly unpredictable fasting blood sugar
  • Risk of nocturnal hypoglycemia especially in elderly
  • People who have unexpected exercise e. g. in policemen, sportsmen
  • Critical patients like patients with hepatic and renal disease, ICU patients, perioperative
  • Patients who have weight gain problems with standard insulin.

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