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Insulin therapy: Where are we now?

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Insulin therapy: Where are we now in 2018

This module deals with the:

  • Natural history of diabetes
  • Insulin initiation
  • Insulin intensification
  • Novel insulin preparations
  • Practical case studies

Natural History: Key Learnings

  • There is progressive loss of insulin secretion with increasing duration of disease1
  • Glycaemic control deteriorates over time in diabetes
  • Initiation and intensification of insulin therapy is key to bring long term control

Legend: OADs, oral antidiabetic drugs; UKPDS, UK Prospective Diabetes Study.2,3


Expert comment: Patients now live long enough with diabetes and will require insulin.12

Type 2 diabetes is a progressive disease marked by a deterioration in β-cell function and progressive insulin resistance. The natural history is progressive and complex. Increasing insulin resistance characterises the prediabetic state. When β-cells function well, insulin resistance results in compensatory hyperinsulinaemia, which maintains relatively normal glucose metabolism.

In this compensated, insulin-resistant state, individuals may have either normal glucose tolerance or IGT but not diabetes. Eventually, the β-cells begin to fail, and insulin secretion falls, resulting in postprandial hyperglycaemia and further loss of insulin secretion. Fasting hyperglycaemia and hepatic overproduction of glucose then occur, resulting in overt diabetes, which may or may not be diagnosed in a timely manner. This process typically begins 4 to 7 years prior to diabetes diagnosis.

Importantly, although early type 2 diabetes may be asymptomatic, evidence suggests that the degree of associated hyperglycaemia may be severe enough for microvascular complications of diabetes to begin to develop.1


Insulin initiation: Key learnings

  1. Understand the factors that influence insulin initiation and adherence4-11
  2. Understand the insulinisation journey

Expert comment: Insulin usage is a journey of titration, intensification and change.
We need to accept that basal insulin will fail also, as the oral medication failed.


Basal failure – Key symptoms

Expert comment: Here are four symptoms/pointers to indicate a need for change; so do not apologise, take a decision to intensify or change the insulin.



Expert comment: The clinician has multiple options of intensification.12-17 The principle is to continue to monitor those using basal insulin regimens (NPH or a long-acting analogue [insulin detemir, insulin glargine]) for need for short-acting insulin before meals or premixed insulin.

Also monitor those using premixed insulin once or twice daily for need for further injection of short-acting insulin before meals or change to mealtime plus basal regimen


Expert comment: Basal insulin alone is usually the optimal initial regimen. It is usually prescribed in conjunction with 1–2 non-insulin agents. In patients willing to take more than one injection and who have higher HbA1c levels (≥9.0% [≥75mmol/mol]), twice-daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines).

When basal insulin has been titrated to an acceptable fasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime insulin, consisting of 1–3 injections of a rapid-acting analogue.18


Expert comment: A less-studied alternative – progression from basal insulin to a twice-daily premixed insulin – could also be considered; if this is unsuccessful, move to basal plus mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing glucose levels as reported by the patient.

Non-insulin agents may be continued, although insulin secretagogues (sulphonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilised.18

In January 2017, the EASD revised their guidance and allows or encourages switching between insulin regimens, adding a GLP-1RA and even switching at a fuller intensification level when treatment goals are not met.


Key messages:

  1. Do not feel trapped in a chosen regimen
  2. Keep metformin on board when you intensify with insulin19
  3. Comprehensive education regarding self-monitoring of blood glucose, diet, exercise and the avoidance of, and response to, hypoglycaemia are critical in any patient on insulin therapy.

Insulin dose, HbA1c and weight.


From Miccoli R, et al.20


Intensification strategies

Expert comment: If metformin is tolerated, keep it on board as it reduces insulin requirement and mitigates against the weight gain.


Expert comment: An important point in choosing a strategy of moving from Premix BID to TID is to remember the need to down-titrate the morning dose.


Expert comment: Very often the basal insulin is not sufficient, and a useful guide is that the basal insulin should be in the order of 50% of the total insulin, including the short acting insulin.


Novel insulins

Expert comment: Newly introduced is the first fully soluble insulin combination product consisting of ultra-long-acting insulin degludec (70%) and rapid-acting insulin aspart (30%).21


Expert comment: The superiority of IdegAsp is somewhat marginal, but is useful in particular patients.


Expert comment: Insulin delivery systems/pens have improved greatly, but despite the advantages of insulin pens over vial and syringe, there are many issues that can reduce the ease of insulin pen use, and which may affect adherence to insulin regimens.

These include the need to reduce injection-site bruising, injection force, and the length of push-button extension on pens that may make it difficult to inject with or manipulate among people with small or weak hands – this may also reduce the flexibility for the user, as they must depress the push-button with their thumb and usually in their dominant hand.

Other factors that may hinder pen use among some patients is a lack of awareness, perceived cost and reduced confidence in the device.


Expert comment: Insulin glargine remains the gold standard of basal insulin therapy.12,23-36


Expert comment: The term “biosimilar” is largely a regulatory designation. It is important to note that the differences in biotechnological manufacturing processes mean that biosimilar products cannot be described as identical.

However the BASAGLAR (Biosimilar) of insulin glargine (Lantus) has shown similar responses.37-40


Adapted from Reference 41


U300 is a highly concentrated insulin which is particularly useful in patients requiring large amounts of insulin.


Expert comment: Clinicians should think about insulin at every stage of the evaluation of a type 2 diabetes patient who is not at target.12


Expert comment: This summary slide can be very useful to address issues in clinical practice.

Key messages

  1. The natural history of diabetes makes the need for insulin therapy inevitable at some point in the clinical course in the majority of patients
  2. There exists clinical inertia both at the level of insulin initiation and intensification
  3. Advances in insulin therapy include emergence of clones, biosimilars, protraction of insulin action, high concentration insulins, ultra-short acting insulins, and insulin + GLP-1 RA co-formulations
  4. The benefits of tight glycaemic control early in the time course of type 2 diabetes is seen in the prevention of complications many years later – legacy effect.

Answer Questions 1-6 below + proceed to Case Studies »


NOTE: This article was made possible by an unrestricted educational grant from Sanofi, which had no control over content.

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