Drug Review - Insulin

Introduction

What are the available insulin preparations and how are they classified?

Which insulins to use?

Human insulins vs. analogue insulins

Bio-similar insulins vs. originator insulins

When should insulin be initiated?

Indications to initiate insulin

How should insulin therapy be initiated?

Initiating and titrating basal insulin as a 3rd anti-diabetic agent

Escalating to pre-mixed insulin

Escalating from basal insulin to a “basal-plus” insulin regimen

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The discovery of insulin in 1921 by Banting and Best was one of the most dramatic and important milestones in medicine. Insulin is life saving in type 1 diabetes where it is essential for survival. However, its greatest utility today is in type 2 diabetes when it is needed for glycaemic control.

INTRODUCTION 

Although insulin resistance is a key component in the pathophysiology of type 2 diabetes, with time, declining beta cell dysfunction results in many patients requiring insulin therapy to maintain optimal glycaemic control. Despite the well-established benefits of optimal glycaemic control, there exists a great deal of inertia to initiating insulin therapy, both on the part of clinicians and patients [the other type of “insulin resistance”]. 

Some of the factors preventing insulin initiation include concerns of hypoglycaemia, weight gain, fear of injections and complexity of insulin self-management. As a result, there are delays of up to seven years in treatment intensification despite suboptimal glycaemic control on two or three oral glucose lowering drugs.^1,2 On the other hand, insulin may sometimes be initiated too early when glycaemic control could just as easily be  achieved with less expensive and less complex oral therapies and with fewer side- effects. Glycaemic control is the key factor, as there is no evidence to suggest that achieving glycaemic control with insulin is more beneficial than achieving the same level of control with any other agent. However, in some patients with type 2 diabetes, due to significant beta-cell failure, only the use of insulin will be enable them to achieve their individualised HbA_1C target.

Since the introduction of human insulin in the 1980’s there has been significant development in this therapeutic area. A large number of options in insulin therapy now exist, including human regular and intermediate insulins, rapid-acting and basal insulin analogues, newer ultra-long-acting and concentrated [U300] basal analogues, as well as various mixes. This section will review the issues pertinent to insulin use in the primary healthcare setting, i.e.

a. What are the available insulin preparations?
b. Which insulins are suitable for use in type 2 diabetes?
c. When should insulin be initiated?
d. How should insulin be initiated and prescribed?

Complex insulin regimens will not be discussed.

WHAT ARE THE AVAILABLE INSULIN PREPARATIONS AND HOW THEY ARE CLASSIFIED? 

Table I explains the terminology used in classifying insulins, and 
Table II is a description of the time-action profiles for insulin preparations available in South Africa.  Insulin Preparations in South Africa shows the cost of these insulin preparations in the private-health sector.

Table I: Insulin terminology and classification 

By production source	Animal insulin	Extracted from pig or cows (porcine or bovine)
	rDNA insulin	Synthesised using recombinant DNA technology
Similarity with human insulin	Human insulins	Have the identical amino acid sequence and physico-chemical properties as native human insulin
	Analogue insulins	Are insulins that do not exist in nature; their amino acid sequence and/or physico-chemical properties have been altered. These changes can be used to speed up the absorption and action of insulin (rapid-acting analogues), or delay its absorption and prolong its action (long-acting analogues)
By insulin concentration	U100 insulins	This is the number of units of insulin in each millilitre (ml) of the insulin solution. U100 insulin contains 100u/ml
	U300 insulins	U300 insulin contains 300u/ml
By onset of action	Short acting	Regular human insulins (identical to human insulin but in a soluble solution) are absorbed within ½ hour and have a peak action within 3.5 hours. This is called short acting insulin
	Intermediate and long-acting insulins	Other insulins are classified relative to regular insulin. Intermediate-acting human insulins have a slower absorption and longer duration of action by adding protamine (NPH) or excess zinc ions (Lente). Some analogue insulins have been altered to either be faster acting than regular insulin (rapid-acting analogues), or to prolong its action (long-acting or ultra long-acting analogues
By the timing of the insulin needed in relation to meals	Prandial (mealtime or bolus) insulin	This is insulin delivered with the aim of regulating the rapid blood glucose rise after meals. This can be accomplished with either short or rapid acting insulin injected before the meal
	Basal insulin	Insulin requirements in the post-absorptive and fasting state e.g. overnight, is called basal insulin; the amount required per hour is smaller and needs to be more consistent to regulate hepatic glucose production, which is the main glucose source in the fasting state

 

Table II: Time action profiles of insulins

Type [proprietary name]	Onset	Peak	Duration
Short-acting regular human insulins [Actrapid, Humulin-R, Insuman, Biosulin-R]	30-60 minutes	2-3 hours	Up to 7-8 hours
Rapid-acting analogue insulins Aspart [NovoRapid] Glulisine [Apidra] Lispro[Humalog]	5-15 minutes	1.5-3.5 hours	5-8 hours
Intermediate-acting (basal) human insulins NPH - neutral protamine Hagedorn [Humulin-N, Protaphane, Biosulin-N] Lente – contains zinc [Biosulin-L]	120-240  minutes 90 minutes	4-10 hours 4-8 hours	10-18 hours§ 22-24 hours§
Long-acting (basal) analogue insulins Glargine [Lantus, Optisulin, Basaglar]	120-240 minutes	No peak	Up to 24 hours§
Pre-mixed human (biphasic) insulins 30% Regular + 70% NPH [Actraphane, Humulin 30/70, Insuman, Biosulin 30/70]	30-60 minutes	Dual peak	10-18 hours
Pre-mixed analogue insulins Rapid-acting plus basal Biphasic aspart [NovoMix] Biphasic lispro [Humalog Mix25, Humalog Mix50] Rapid-acting plus ultra-long-acting basal Pre-mixed aspart/degludec [Ryzodeg]	5-15 minutes 5-15 minutes	Dual peak Dual peak	10-16 hours >24 hours

§The duration of action of intermediate and long acting insulins is dose dependent. For example, the duration of action of insulin detemir 0.2u/kg and 0.4u/kg is 12 and 20 hours respectively ³. At lower doses, basal insulin may need to be dosed twice daily depending on individual patient responses. 

WHICH INSULINS TO USE?

 

HUMAN INSULINS VS. ANALOGUE INSULINS/strong>

For each instance of insulin use, the practitioner and patient is faced with a choice of opting for a human insulin or an analogue insulin. This section describes some clinical trial evidence to guide the rational use of insulin in the treatment of type 2 diabetes.

Rapid-acting analogues vs. short-acting regular human insulin

All 3 currently available rapid-acting analogue insulins (lispro, glulisine, aspart) have been compared to regular human insulins as part of basal bolus therapy in patients with T2DM.⁶ In addition, there have been a number of meta- analyses of trials comparing rapid-acting insulin analogues and short-acting regular human insulin See: Summary of Meta-analyses and Systematic Reviews comparing Rapid-acting Insulin Analogues to Short-acting Regular Human Insulin. ^7,8,9,10,11 In summary, these meta-analyses showed that HbA_1C reductions with rapid acting-analogues and regular human insulin were similar, while post-prandial glucose control with analogues was found to be superior. There was no difference in the incidence of hypoglycaemia. The rapid-acting analogues have the benefit of a rapid onset of action, making it convenient to inject just prior to eating (as opposed to injecting 30 minutes before eating for human insulin).

Recommendations: Rapid-acting insulin analogues are preferred to short-acting human insulins, for improved convenience and for post-prandial glucose control, when the cost is not prohibitive.

Basal insulin analogues vs. human basal insulin (NPH)

Two separate systematic reviews have compared the outcomes of treatment with NPH insulin and basal insulin analogues.^12,13 In summary, these reviews showed similar HbA_1C reduction when using either type of insulin with no difference in long-term outcomes including morbidity and mortality. However, there were lower rates of symptomatic and nocturnal hypoglycaemia with basal insulin analogues. Insulin detemir has also been shown to have a weight advantage compared with NPH and insulin glargine.¹³ In summary, long-acting basal insulin analogues do not offer better glycaemic control when compared to human basal insulins. Although the rates of severe hypoglycaemia are not lower, long-acting analogue insulins are less likely to cause nocturnal hypoglycaemia when compared with human basal insulins.

Recommendations: Since human basal insulins are historically less expensive than analogue insulins it is cost- effective to initiate basal insulin therapy with a human basal insulin, except when the risk of hypoglycaemia is unacceptably high. Patients with subsequent recurrent nocturnal hypoglycaemia should then be switched to an analogue basal insulin. When the cost differential between human basal and analogue insulins is not great, initial treatment with an analogue basal insulin is preferred.

 

BIO-SIMILAR INSULINS VS.ORIGINATOR INSULINS

Definition of biosimilars, clones and generics

As opposed to simple  chemical  drugs  that  are  usually  small molecules produced synthetically, biological agents such as insulin are produced by complex means using microorganisms, cell or tissue culture. Generics of small molecules, due to their relative simplicity, are produced identically to the originator with only evidence of similar bio-availability required by regulatory bodies. Biological agents are large complicated molecules with equally complicated production protocols that remain the proprietary information of the original manufacturer after expiry of the molecule’s patent. Therefore, a biosimilar, while intended to have the same clinical effect as the originator, is produced by different means to the originator. As minor changes to a complex molecule could impact  on  efficacy  and safety, regulatory authorities require head-to-head comparison with the originator in the registration of a biosimilar. This is likely to impact on the cost benefits of biosimilars compared with generics.¹⁴ A clone is identical to the originator in every detail and often produced by the same manufacturer. In South Africa, insulin glargine, a basal insulin analogue, is available as a clone (Optisulin®) and a biosimilar (LY Iglarg or Basaglar®).

Biosimilar insulins in South Africa

This biosimilar insulin glargine has been evaluated in comparison to the originator in terms of efficacy and safety in patients with type 1 and type 2 diabetes mellitus. The Element 1 study was a phase 3, randomized, 52 week trial in patients with type 1 diabetes, and will not be discussed in this guideline.¹⁵ In the Element-2 study, patients with type 2 diabetes on up to 2 oral agents were randomised to LY Iglarg or originator insulin glargine for 24 weeks.¹⁶ LY Iglarg was non-inferior to insulin glargine for change in HbA1C from baseline. Adverse events, allergic reactions, weight change, hypoglycaemia and insulin antibodies were similar between treatment groups.

A biosimilar human 30/70 premix insulin (Biosulin 30/70®) has also been compared to originator premix human insulin, and demonstrated equivalent glycaemic control and safety.¹⁷

Recommendations: Currently in South Africa we have access to 3 preparations of insulin glargine (originator, clone and biosimilar). There are also biosimilar insulins for human short-acting, intermediate-acting and premix insulins. These are all registered with the Medicines Control Council. Based on current evidence, the efficacy and safety profiles of these preparations are similar. While it is not recommended that patients with stable glycaemic control be unnecessarily switched to an alternative preparation, if needed, this should be done on a dose for dose basis.When treatment with human or analogue insulin is initiated, the insulin with the lowest acquisition cost within the class is preferred.

 

WHEN SHOULD INSULIN BE INITIATED

The evidence base for insulin therapy

The question often arises – should insulin be initiated early in the course of type 2 diabetes for some or other perceived benefit, even when glycaemic control is achievable with other therapies, or should insulin be delayed for as long as possible because of possible harms. Two randomised controlled clinical trials have examined the question regarding early insulin therapy.^18,19 These and other studies are discussed below.

a. United Kingdom Prospective Diabetes Study (UKPDS)¹⁸

The 10-year follow-up of the UKPDS showed that newly diagnosed patients with type 2 diabetes that were randomised to receive intensive treatment with a sulphonylurea (SU) or insulin had similar relative reductions in risk for microvascular disease. Initial treatment with insulin in newly diagnosed patients was not superior to SU for any outcomes. However, insulin treated patients gained significantly more weight and had a significantly higher rate of hypoglycaemia.¹⁸ Insulin was not superior to diet / conventional therapy (where patients were only treated when the fasting plasma glucose exceeded 15mmol/L) for macrovascular and mortality outcomes. In an observational study, 10 years after the trial had completed, both early insulin and SU treatment was equally associated with lower rates of any diabetes-related end-point (9%, P = 0.04), microvascular disease (24%, P = 0.001), myocardial infarction (15%, P=0.01) and death from any cause (13%, P = 0.007) when compared to conventional treatment.²⁰

Unfortunately, these trials (UKPDS) were not designed to study the safety of one drug against another. In the UKPDS 34 study, for example, metformin reduced macrovascular events and mortality in obese patients whereas insulin did not.²¹ However, because of the trial design, it is not possible to determine whether the different outcomes were due to an  improved  safety of metformin, or a potential harm of insulin therapy. The conclusion is that improving glycaemic control with insulin reduces microvascular complications to the same extent as sulphonylureas, compared to placebo, and that insulin therapy should be initiated whenever glycaemic control is not possible with other glucose lowering drugs.

b. Outcome Reduction with an Initial Glargine Intervention Trial (ORIGIN)¹⁹

The ORIGIN trial tested the hypothesis that normalisation of fasting plasma glucose with basal insulin would reduce cardiovascular disease in patients with diabetes and intermediate dysglycaemia, as well as prevent the progression of IFG/IGT to diabetes. The trial showed no reduction in cardiovascular disease in patients treated with insulin glargine for a median duration of 6 years. Patients with intermediate dysglycaemia  treated  with basal insulin were 28% less likely to develop diabetes compared with controls but at the cost of weight gain and increased hypoglycaemia. There was no increased risk of cancer associated with insulin glargine in this trial (insulin dose range 0.19 to 0.53u/kg; duration 6 years). A meta-analysis of insulin studies confirmed that insulin had no benefit over placebo/diet on mortality or cardiovascular outcomes (similar to UKPDS and the ORIGIN studies).²² These trials show that initiating insulin therapy early, when glycaemic control is not poor, carries no particular benefit over other agents, but does increase hypoglycaemia and causes weight gain.²²

c. Other safety studies

Observational studies have reported an increased cardiovascular and mortality risk with insulin therapy when compared to other therapies^.23,24,25,26 However, observational data do not allow causal inferences. Insulin therapy has also been associated with worse outcomes in patients with pre-existing cardiovascular disease in the DIGAMI 2 and BARI-2D trials.^27,28 A network meta-analysis of mainly short-term randomised controlled trials reported no differences in the cardiovascular safety for any of the available anti-diabetic therapies.²⁹

d. Efficacy studies

In the meta-analysis by Liu et al., basal insulin added to metformin as a 2_^nd line agent resulted in similar HbA1C reductions to SUs and thiazolidinediones (TZDs) (~0.85%), and was less than GLP- 1 receptor agonists (GLP-1RAs) and biphasic insulin.³⁰Weight gain was not statistically different between the three treatments (SU, TZD and basal insulin), and hypoglycaemia was significantly lower with TZDs.

In the meta-analysis by McIntosh et al.,  basal  or  biphasic  insulin added as  a  3^_rd  anti-diabetic  agent  to  metformin  and  SU lowered HbA1C by 1.17%, and was not statistically different to the reductions with TZDs (0.96%),  DPP-4  inhibitors  (0.89%) or GLP-1RAs (0.96%).³¹ Insulin and TZDs were associated with weight gain, DPP-4 inhibitors were neutral and GLP-1RAs were associated with weight loss.³¹

In the meta-analysis by Palmer et al., all drug classes were equally efficacious compared to insulin, when added to metformin as a 2nd line anti-diabetic agent.²⁹ For 3rd line therapy (added to metformin + SU), TZD and basal insulin were equally efficacious with similar weight gain and hypoglycaemia.²⁹ Insulin treatment was associated with the lowest odds of treatment failure. Insulin and TZDs were more effective than DPP-4 inhibitors for lowering HbA1C and also for avoiding treatment failure.²⁹

The Treating to Target in Type 2 Diabetes (4-T) Study compared 3 insulin regimens in patients with suboptimal glycaemic control, who were taking oral agents (metformin and SU).³² The three- year follow-up of the 4-T study showed that median HbA1C levels were similar for patients receiving biphasic insulin aspart (7.1%), prandial insulin aspart (6.8%), and basal insulin detemir (6.9%) insulin-based regimens. However, the median rates of hypoglycaemia per 100 patients per year were lowest in the basal group (170 episodes), higher in the biphasic group (300 episodes), and highest in the prandial group (570 episodes). In addition, the mean weight gain was higher in the prandial group than in either the biphasic or the basal groups. Other adverse event rates were similar in the three groups. This trial provides a sound basis for the recommendation that if insulin therapy is considered as the 3rd line option of treatment, it should be initiated using a basal insulin regimen i.e. adding an intermediate or long-acting insulin at bedtime.

Caution is advised in interpreting the above meta-analyses and studies in the South African context, as the data on SUs in the meta-analyses refer mainly to glibenclamide and glimepiride (which have higher rates of hypoglycaemia and weight gain compared to gliclazide), and also because the data on basal insulins is based largely on analogue insulin use, which have lower rates of hypoglycaemia and weight gain (in the case of insulin detemir) than NPH insulins.

e. Evidence-based recommendations for insulin in type 2 diabetes

The current evidence for insulin therapy is as follows:

1. Intensive glycaemic control with insulin therapy reduces microvascular complications.¹⁸
2. There is no evidence that insulin therapy is associated with better outcomes or particular advantages,  when  compared  to other therapies that can achieve similar glycaemic control^18,19,27,28
3. There is inconclusive evidence to suggest that insulin therapy may be associated with worse cardiovascular and mortality outcomes when compared to other therapies that can achieve similar glycaemic control.^{21,23,24,25,26,27,28}
4. In stable patients without metabolic decompensation, insulin treatment should be initiated with a basal insulin.³²
5. In multiple analyses, basal insulin is not more effective than other anti-diabetic agents in lowering HbA_1C.^29,30,31 Additionally, it is a complex treatment requiring additional resources for education and titration. Insulin is therefore not recommended as a 2^nd line anti-diabetic agent in stable patients, and should be one of the options available as a 3^rd line anti-diabetic agent.

 

INDICATIONS TO INITIATE INSULIN 

The indications for insulin treatment in non-pregnant adults are:

1. At diagnosis, or at any stage of type 2 diabetes, when there is metabolic decompensation with any of the following features:

• Catabolism (marked weight loss)
• Fasting plasma glucose levels >14 mmol/l 
• Random glucose levels consistently >16.5 mmol/l 
• HbA1C > 10%
• Presence of persistent ketogenesis, ketoacidosis or hyperosmolar non-ketotic state

The management of this category of patient is not the subject of this guideline; these patients should be managed intensively, either with a basal-bolus or premix insulin regimen, and specialist referral is recommended.

2. For stable patients without metabolic decompensation, insulin should be considered as a treatment option when glycaemic control is not achieved or maintained with 2 or more other anti-diabetic agents.

 

HOW SHOULD INSULIN THERAPY BE INITIATED?

The numerous insulin preparations and combinations can make insulin therapy complicated and confusing for the primary care practitioner. The following recommendations can be made to simplify decision-making (based on the discussion above):

1. Consider the addition of insulin to an existing 2-drug regimen when glycaemic targets are no longer met. Other options will include adding a 3rd oral anti-diabetic agent or a GLP-1 receptor agonist. 
2. When adding insulin as a 3rd anti-diabetic agent, the choice of insulin regimen should be a once daily basal insulin regimen to minimise hypoglycaemia and weight gain.
3. Choose insulins with a low acquisition cost. There are no substantial differences within a particular class of insulins to justify large differences in cost. Bio-similar insulins and clones are acceptable. If costs are similar, a basal insulin analogue is preferred to human insulin. When the cost-differential is high, start with a human basal insulin.
4. If nocturnal hypoglycaemia is a limiting factor to achieving glycaemic control with a human basal insulin, switch to a long- acting basal insulin analogue (if not already in use).
5. When glycaemic control deteriorates with a 3-drug regimen that includes an adequately titrated basal insulin, treatment should be escalated to either a premix insulin regimen, or a “basal plus” regimen (where the basal insulin is maintained and prandial doses of short acting insulin is added). A third alternative would be the addition of a GLP-1 receptor agonist to the basal insulin regimen.
6. When glycaemic control deteriorates with a triple oral regimen (e.g. metformin + SU + TZD/DPP-4 inhibitor/SGLT2 inhibitor), continue metformin treatment and initiate insulin treatment with a twice-daily premix insulin, or refer the patient for basal- bolus insulin therapy.
7. Use only insulin pen delivery devices (disposable pens or pen refills); vials and syringes should not be used.

Prior to initiating insulin treatment, it is important to ensure that there are adequate resources available to support the patient in initiating and  adjusting insulin treatment.  

Note  that in the 4T study discussed above, 28% and 63% of patients achieved an HbA1C <7% at 1 year and 3 years respectively.^32,33To achieve this result, patients had to be willing to perform self-blood glucose monitoring, they had access to dietitians and diabetes educators, they had clinic visits at weeks 0,2,6,12,24,38 and 52 weeks (7 face-to-face visits within a year), and frequent interim telephonic contact and support. For the latter 2 years of the study, clinic visits occurred every 12 weeks, again with interim telephonic contact. Before each clinic or telephone contact, patients  were  required  to  perform  pre-breakfast and pre-supper SBGM for 3 consecutive days. In addition they performed an 8-point glucose profile (including at 03h00) at week 0,12,24,38 and 52, and also tested blood glucose whenever they felt unwell. Glucose test-strip supply was unlimited and uninterrupted. A computer system guided insulin dose titration and also monitored investigator and patient  compliance  with the monitoring and titration protocol. The target fasting glucose was 4.0 to 5.5 mmol/L and the post-prandial glucose target was 5.0 to 7.0 mmol/L.

This type of protocol for insulin therapy is commonplace, and some trials have used even more rigorous SBGM and titration algorithms. An inability to offer similar support services and “forced” titration protocols to patients when initiating insulin therapy is unlikely to achieve similar results to that seen in clinical trials, and is likely to result in treatment failure.

INITIATING AND TITRATING BASAL INSULIN AS A 3RD ANTI-DIABETIC (refer table below)

Table III: Independent risk factors for severe hypoglycaemia  

Independent risk factors for severe hypoglycaemia

Insulin or sulphonylurea use

Intensive glucose control

Use of 2 or more oral glucose lowering drugs

Older age

Diabetes duration

Hypoglycaemia unawareness

Impaired cognitive function

Low body mass index

Renal impairment

Microvascular complications

 

1. Ensure that there are adequate resources available to support the patient in initiating and adjusting insulin treatment: protocols for monitoring and titration, regular access to a diabetes nurse educator to be instructed on injection technique, SBGM, management of hypoglycaemia, hyperglycaemia and sick-days, access to frequent doctor and clinic visits (6 per year), telephonic support between visits, uninterrupted supply of insulin and glucose test strips.
2. Continue all oral agents.
3. Initiate 10 units of basal insulin (or 0.2u/kg) using an intermediate or long-acting insulin (use insulins with a low acquisition cost; clones and biosimilar insulins are acceptable).
4. Titrate dose
5. If unexplained nocturnal hypoglycaemia occurs, instruct the patient to reduce the basal insulin dose by 10% or 2-4 units, to stop titration, and to inform the doctor if it occurs again. If there are persistent episodes of nocturnal hypoglycaemia then switch to a long-acting insulin analogue (if not already in use).
6. Consider using a long-acting insulin analogue (glargine, detemir) in the following situations:

• If nocturnal hypoglycaemia is problematic with NPH insulin
• In those who require assistance from a carer or healthcare professional to administer their insulin injections
• In those whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemic episodes
• When circumstances exist where the risk of severe hypoglycaemia and/or its potential consequences can be significant and/or catastrophic.

 

ESCALATING TO PRE-MIXED INSULIN

1. Ensure that there are adequate resources available to support the patient in initiating and adjusting insulin treatment: protocols for monitoring and titration, regular access to a diabetes nurse educator to be instructed on injection technique, SBGM, management of hypoglycaemia, hyperglycaemia and sick-days, access to frequent doctor and clinic visits (6 per year), telephonic support between visits, uninterrupted supply of insulin and glucose test strips.
2. Continue with metformin only and stop all other anti-diabetic drugs.
3. Insulin dose:
   • Split the existing basal insulin dose to give 2/3 as a premix   in the morning before breakfast and 1/3 as a premix in the evening before supper
   • If the patient is not already on a basal insulin (e.g. a patient on 3 oral drugs, or 2 oral drugs and a GLP-1RA), then initiate premix insulin at a total dose of 0.3 u/kg given as 2/3 in the morning before breakfast and 1/3 in the evening before supper. Use premixes with a low acquisition cost.
4. The patient must monitor his or her finger prick glucose before breakfast and before supper. The target glucose will vary depending on the individualised target HbA1C (Refer to Chapter 8)
5. Titrate the pre-breakfast insulin dose to achieve the pre- supper target glucose level, and vice versa.
6. Titration frequency varies, depending on circumstances. For example, titration may take place daily if the patient is under direct supervision in hospital, weekly if  the patient needs to see the healthcare provider to supervise titration as an out-patient, or every three days if the patient has good numeracy skills and is able to self-titrate without supervision.
7. If unexplained hypoglycaemia occurs, instruct the patient  to reduce the last injected insulin dose (preceding the hypoglycaemic event) by 10% and to stop titration. If the patient experiences recurrent episodes of hypoglycaemia then they should contact their doctor, who could then consider an analogue insulin pre-mix (if not already in use) or refer to a specialist.

ESCALATING FROM BASAL INSULIN TO A "BASAL-PLUS" INSULIN REGIMEN

Patients sub-optimally controlled with an existing basal insulin regimen may improve their glycaemic control by targeting post- prandial hyperglycaemia. A short or rapid-acting insulin can be added before the largest meal of the day, or before the meal that has the greatest post-prandial glucose excursion. This short/ rapid acting insulin can then be titrated based on the SBGM level before the next meal. Further doses of short or rapid acting insulin can be progressively added for the other meals that are associated with post-prandial hyperglycaemia, until a complete basal-bolus regimen is used. Oral agents other than metformin should be progressively discontinued to reduce the complexity of the regimen.

Authors: Aslam Amod, Joel Dave and Zane Stevens

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