Insulins

Introduction

Insulin is used in the treatment of diabetes mellitus.

Generally, all people with type 1 diabetes mellitus need insulin treatment; many individuals with type 2 diabetes will require insulin as their beta cell function declines over time.

Indications

Insulin therapy should be considered in the following conditions.

Type 1 diabetes.
Inadequate glycemic control on optimal dose and number of oral glucose lowering drugs in Type 2 diabetes.
Severe hyperglycemia on presentation.
Short-term use in acute illness or surgery, pregnancy, breast-feeding and severe metabolic decompensation (e.g. diabetic ketoacidosis).
Difficulty distinguishing types of diabetes.

Although the peak incidence of type 1 diabetes occurs around the time of puberty, approximately 42% of cases present after 30 years of age.

Types of Insulins

Two types of insulins are currently used in Malaysia.

Human insulin derived by recombinant technology

After regular insulin (short-acting) is injected subcutaneously, the hexamers that have formed dissociate into dimers and monomers that are absorbed. This causes a delay in rise of insulin concentrations in the blood stream, resulting in a need to inject at least 30 minutes before the meal to best cover post-meal glycemic excursions.
Neutral protamine Hagedorn (NPH) insulin is a crystallized suspension of human insulin, protamine and zinc in a neutral buffer that delays the release of the insulin into the bloodstream (intermediate-acting).
Basal intermediate acting insulin should be administered pre-bed (preferably not earlier than 10 pm) because of the risk of hypoglycemia in the early hours of the morning if given earlier.

Insulin analogues which are genetically modified human insulin.

Rapid-acting insulin analogues (e.g. insulin lispro, lispro-aabc, aspart, faster aspart and glulisine) have faster onset and shorter duration of action than regular insulin for pre-meal coverage.
Long-acting analogues (e.g. insulin glargine, determine, degludec) have a longer, flatter and more predictable day-to-day profile than NPH for basal coverage (i.e. lower hypoglycemic episodes).

Based on their pharmacokinetic profiles, types of insulin are

Prandial (bolus)

Rapid or short-acting insulin.
To cover the extra requirements after food is absorbed.

Basal

Intermediate or long-acting insulin.
To suppress hepatic glucose production and maintain glucose levels at target in the fasting state.

Premixed

Biphasic insulin that incorporates both the short or rapid-acting insulin with intermediate or long-acting insulin in a single preparation.
Should always be dosed before meals because the fast-acting component is meant to cover prandial intake.

Disadvantages

The major drawbacks associated with insulin therapy are

Weight gain
Hypoglycemia

Glycemic Control Targets

Fasting or pre-prandial

Outpatient: 4.4-7 mmol/L
General ward or ICU admission: 7.8-10 mmol/L. Initiate insulin therapy if blood glucose >10 mmol/L.

Post-prandial (at least 90 minutes after meals)

4.4-8.5 mmol/L

HbA1c

<7% for most
≤6.5% for younger age and healthier patients
7.1-8% for elderly patients and patients with co-morbidities (e.g. advanced CVD, heart failure, dementia, advanced renal failure)

Insulin Initiation and Titration in Type 2 Diabetes Mellitus

An ideal insulin regimen should mimic the physiological insulin response to meals and endogenous hepatic glucose production.

The choice of insulin regimen should be individualised, based on the patient's glycemic profile, dietary pattern and lifestyle.

Initiate basal insulin first.

In addition to oral and non-insulin injectable agents.
Initial dose: 0.1-0.2 units per kg (minimum 10 units, up to 15 to 20 units) daily.
If fasting glucose levels are very elevated (>13.9 mmol/L), A1C is >8 percent, or if a patient is known to be very insulin resistant, initial doses of basal insulin can be higher (e.g., 0.3 units per kg or up to 15 to 20 units daily as an initial dose).

Titrating dose.

The basal insulin dose may be increased by 2 to 4 units approximately every 3 days to achieve the target range if the mean fasting glucose is above target (7.2-7.7 mmol/L).
Titration can be more aggressive if fasting glucose levels are very elevated (>13.9 mmol/L) or if a patient is known to be very insulin resistant.

Initiate prandial insulin if persistent elevation in A1c with fasting glucose in target range.

A typical starting dose is approximately 4 to 6 units or 10% of basal insulin dose. The dose can be increased every 3 days until the postprandial blood glucose target is achieved.
Check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner before bed to further adjust insulin regimen.
Prandial insulin dose increases depend on how much prandial insulin the patient is using. As a rule of thumb:

≤10 units - Increase by 1 unit
11 to 20 units - Increase by 2 units
>20 units - Increase by 5 units (or more, depending on patient insulin resistance, meal size, and content)

A more complex method for adjusting pre-meal insulin is to match insulin delivery to the anticipated glucose excursion with meals. Many patients benefit from specific training in carbohydrate counting, which requires some arithmetical computations that some patients find difficult or burdensome.
The ability to inject rapid-acting insulins 10 to 15 minutes before meals (as opposed to the 30 to 45 minutes before the meal with regular [short-acting] insulin) is more convenient and may improve adherence.

Alternatively, convert to premixed insulin.

The major drawback of premixed insulin is limited flexibility in adjusting doses.
However, premixed insulin is a reasonable option for patients with type 2 diabetes who are doing well on a stable, fixed ratio of short- and intermediate-acting insulin, or who are able to modify their diets to match the kinetics of premixed insulin.
Premixed insulin works best when there is little day-to-day variability in breakfast, lunch, and dinner (with a small lunch) or when people are so insulin resistant that they are unlikely to develop hypoglycemia after smaller meals.
To initiate, calculate the total daily dose based on weight (0.2 units per kg [minimum 10 units, up to 15 to 20 units] daily) or based on prior insulin dose. One approach is to administer two-thirds of the total daily dose before breakfast and one-third before dinner. Premixed insulin should be dosed relative to meal intake and may need to be reduced for smaller meals.

NOTE: Physiologic replacement of insulin with "basal-bolus" insulin therapy should be started as early as possible following the diagnosis of type 1 diabetes.

Initiation and Optimisation of Insulin Therapy

General Guidelines for Long Term Use of Insulin

Requirements of high dose of insulin (total daily dose >1.5-2 IU/kg) should prompt a search for an underlying cause such as non-adherence or incorrect injection technique.

In general, total daily dose of prandial insulin should not be >50% of total daily dose.

Monitor weight gain.

Read up insulin injection techniques at a separate post.

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