Long-acting insulin analogues. Drug selection by means of the System of Objectified Judgement Analysis (SOJA)

Generics and Biosimilars Initiative Journal (GaBI Journal). 2022;11(1):25-34.
DOI: 10.5639/gabij.2022.1101.005

Published in: Volume 11 / Year 2022 / Issue 1
Category: Review Article
Page: 25-34
Visits: 348 total, 3 today
Keywords: Degludec, detemir, diabetes mellitus, glargine, long-acting insulin analogues, NPH insulin

Author byline as per print journal: Robert Janknegt, PharmD, PhD; Marloes Dankers, MSc

Abstract:
Objectives:
The increasing number of long-acting insulin analogues makes it difficult for general practitioners to have sufficient knowledge of each individual insulin formulation and device. Reducing the number of different insulin analogues used, based on rational criteria, allows physicians and pharmacists to build experience with a more limited set of medicines and to optimize patient information. The costs of newer formulations also need to be considered.
Methods: In this study long-acting insulin analogues are compared by means of the System of Objectified Judgement Analysis (SOJA) method. The following selection criteria were applied: effectiveness, safety, tolerability, ease of use, and applicability. Concrete sub-criteria for each selection criteria were defi ned.
Results and Conclusions: We found almost identical scores for the long-acting insulin analogues. Therefore, acquisition cost and individual patient characteristics should be used to determine the choice of formulary products. Glargine 100 IU/mL (biosimilar or originator) is the cheapest option in most cases. It should be noted that ‘good old’ Neutral Protamine Hagedorn (NPH) insulin is still a good treatment option from a formulary perspective NPH insulin is also likely to be cheaper than biosimilar glargine in most countries.

Submitted: 24 December 2022; Revised: 22 March 2022; Accepted: 24 March 2022; Published online first: 31 March 2022

Introduction

The incidence and prevalence of both diabetes mellitus type 1 and (especially) type 2 has been steadily increasing. There are now about 60 million people with diabetes in the European Region, or about 10.3% of men and 9.6% of women aged 25 years and over [1].

A substantial number of type 2 diabetes patients eventually require insulin. Different forms of insulin, such as short-, intermediate- and long-acting insulins are available. According to the guidelines of the Dutch College of General Practitioners ‘Type 2 Diabetes Mellitus in primary care’, (long-acting) NPH-insulin is considered the first choice if insulin treatment is indicated. The insulin analogues insulin glargine 100 U/mL and insulin detemir are considered potential alternatives in specific situations, especially when patients experience frequent night-time episodes of hypoglycaemia. The other analogues, insulin glargine 300 U/Ml and insulin degludec, are not (yet) recommended, because of the lack of evidence-based advantages compared to other long-acting insulins, insufficient knowledge of long-term safety (in the case of insulin degludec), and costs [2].

Despite the Dutch preference for NPH-insulin, insulin analogues, including biosimilars, are prescribed extensively by European physicians [3-5]. In primary health care, insulins account for a high percentage of drug expenditures. The introduction of the first generation long-acting insulin analogues (insulin glargine 100 U/mL and insulin detemir) in the first decade of the 21st century resulted in rapidly increasing dispensing rates and healthcare costs [6-10]. Because the second generation long-acting insulins (insulin glargine 300 U/mL and insulin degludec) are even more expensive than glargine and detemir, they are thought to be responsible for further increases in total insulin expenditures [9].

Therefore, there is a need for practitioners to make more rational choices between the increasing number of long-acting insulin analogues when they prescribe insulin products.

The following insulin analogues are included in this analysis:
degludec (Tresiba)
detemir (Levemir)
glargine 100 IU/mL (Lantus, Abasaglar (biosimilar))
glargine 300 IU/mL (Toujeo)

Insulin degludec is a modified form of human insulin in which the amino acid at position B30 is deleted and the lysine at position B29 is conjugated to hexadecanoic acid via a gamma -Lglutamyl spacer.

In insulin detemir a 14-C fatty acid is coupled to the lysine residue on position 29 of the B chain and threonine is removed at position 30 of the B-chain.

In insulin glargine, asparagine has been replaced by glycine at position 21 in the A-chain and by the addition of two arginine residues to the end of the B-chain, at positions 31 and 32. Both ‘manipulations’ result in a slower absorption, leading to a more gradual absorption profile compared to NPH insulin.

Applied methodology
The System of Objectified Judgement Analysis (SOJA) method is a decision model used to make formulary recommendations, in which the authors prospectively defi ne selection criteria for a given drug group and assign a relative weight to each criterion by consensus between the authors based on their perceptions of their local situation [11]. The more important a given criterion is judged to be, the higher the relative weight that is assigned to it. The properties of the drugs are evaluated per criterion and each individual drug is assigned a score for each criterion; this score being a percentage of the relative weight of this criterion. The closer the drug approaches the ‘ideal’ drug, the higher the percentage score for that criterion. The drugs with the highest overall scores are considered the most attractive ones for formulary inclusion.

A (English, German and Dutch) Medline and Embase search was performed, as well as a search for studies in the Cochrane library and collection of the references from meta-analyses and systematic reviews to obtain relevant studies regarding long-acting insulin analogues. In addition to these searches, the references of review articles on this subject were obtained and incorporated in the analysis when appropriate and these were included in the manuscript. Search terms were degludec, detemir, glargine and NPH.

The present SOJA score has five sets of (sub-) criteria for the selection of long-acting insulin analogues. These criteria are:
Efficacy (the actual positive outcomes and treatment goals)
Safety (the avoidance of negative outcomes, such as hazardous side effects)
Tolerance (the interruption of the care process due to less hazardous, generally transitory, but disturbing side effects)
Ease of use (ease for the patient, for example, dosing frequency)
Applicability (the scope of the treatment freedom (interactions and such) and the ease for the caregiver)

These criteria are specifically described per selection subject (‘operationalised’). All scores were assigned based on a consensus of the authors, see Table 1.

Table 1 pending to upload

Selection criteria

1 Effectiveness
1.1 Risk of late complications
The ultimate goal of T2DM treatment is the minimization of cardiovascular complications (including renal failure), immortality, and microvascular complications (neuropathy).

The score assigned was dependent on the data available regarding risk reduction by the individual insulin analogues.

The criterion was separated into macrovascular complications and microvascular complications.

1.2 Effect on metabolic control
According to the Dutch T2DM guidelines, haemoglobin A1c (HbA1c)-targets depend on age, duration of T2DM and use of other blood glucose lowering drugs. The relationship between HbA1c and cardiovascular outcomes remains to be elucidated, as a result of contradictory study results.

2 Safety
The extent and the severity of adverse effects is another important drug selection criterion. A distinction was made between ‘minor’ side effects, such as gastrointestinal disturbances or skin reactions, occurring in clinical trials (scored under tolerability) and severe or even life-threatening adverse reactions observed with large scale studies of the use of the drugs.

The following aspects were taken into consideration:
2.1 Risk of severe hypoglycaemia
2.2 Cancer and heart failure
2.3 Documentation

Obviously, there is less experience with recently introduced medicines compared with medicines that were introduced earlier. This makes it more uncertain whether the newly introduced medicines are as safe as older medicines. Therefore, this item was scored under the main criterion of safety.

The first two sub-criteria below (number of double-blind clinical studies and number of patients in these studies) are indicative of the overall quality and quantity of the randomized, controlled clinical studies of the drugs. A large number of clinical studies and the large number of patients included in these studies leave no doubt about the clinical efficacy and safety profile of these drugs in the populations studied.

The latter two criteria (number of years available and number of patient days) are indicative of the overall clinical experience with the drug in question. These sub-criteria may introduce a bias to the advantage of older drugs, but this is done intentionally. The safety of a newly introduced drug cannot be guaranteed from only the results of clinical studies, in which only a relatively small number of patients were included and most patients at risk for the development of adverse reactions (e.g. patients with diminished renal function) were excluded. Both the number of patients that have been treated on a worldwide basis and the period that a certain drug has been available are of importance, as it may take time until adverse reactions occur or be recognized.

Number of double-blind comparative clinical studies
5% was given for each study.
Number of patients in these studies
1% was given for every 10 patients included in the above studies.
Number of years available on the market
10% was given for every year that the drug was available on the market.
Number of patient days experience
1% was given for every million patient days.

3 Tolerability
The extent and the severity of adverse effects is another important selection criterion for drugs. A distinction was made between ‘minor’ side effects, such as gastrointestinal disturbances or skin reactions, that occurred in clinical trials and the severe or even life-threatening adverse reactions observed with large scale use of the drugs (scored under safety). The evaluation of the ‘minor’ adverse effects was based on the results of double-blind comparative clinical studies.

The following aspects were considered:
3.1 Mild hypoglycaemia
3.2 Weight gain
3.3 Pain at injection site

4 Ease of use
Because long-acting insulin analogues must be used lifelong, it is of importance that their use is made as easy as possible.

The following aspects were taken into consideration:

4.1 Dosing frequency
A low dosage frequency is of great importance in life-long treatment of diabetes. Patient compliance is best with once daily dosing, although the difference between once and twice daily dosing is not impressive. Patient compliance drops significantly at higher dosage frequencies.

This was scored as follows:

Table pending to upload

4.2 User-friendly administration form
An easy-to-use administration device may increase patient acceptance and compliance.

A pen allows more patient-friendly administration than an injection vial for some patients.

5 Applicability
This criterion is focused on the caregiver. The following aspects are taken into consideration:

5.1 Medication interactions
This criterion is of importance in formulary decision-making since the majority of treated diabetic patients need to take other medications as well. Drug interactions may result in an increased or reduced clinical efficacy of the antidiabetic medicine in question or in a reduction of the clinical efficacy of the other drug, with which the interaction occurs. Interactions may also give rise to increased toxicity of one or both medications. The more frequent these interactions occur and the more serious the consequences are, the lower the score for the drug in question.

5.2 Contra-indications, special warnings, and precautions
Contra-indications, warnings, and precautions may hinder the caregiver in the prescription of long-acting insulin analogues to patients. The score is dependent on the extents of contraindications, warnings, and precautions.

5.3 Dose adjustment
Dose adjustments may be necessary in patients with renal or liver function impairment. When dose adjustment is not necessary, this provides an advantage over a medicine for which adjustments are necessary.

Results

1 Effectiveness
1.1 Risk of late complications
1.1.1 Macrovascular complications
Both diabetes and older age are important risk factors for cardiovascular complications. Coronary heart diseases are the most important causes of death in patients with type 2 diabetes [12]. The cardiovascular risk profile of diabetes patients is comparable to individuals without diabetes who are 15 years older [13].

One large scale study showed similar effects of glargine and standard care on the risk of myocardial infarction, stroke, or cardiovascular death. The co-primary outcomes were non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes, and any of these events plus revascularization or hospitalization for heart failure. The incidence of cardiovascular outcomes was similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first co-primary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; p = 0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second co-primary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; p = 0.27). Only 11 per cent of the patients in the standard therapy group received insulin. A1C values were comparable at baseline and at study end. About 60 per cent of patients in both groups were treated with statins and 75 per cent with inhibitors of the renin-angiotensin system [14, 15].

All studies with detemir and glargine were of insufficient duration and size to be able to show a relevant beneficial effect (let alone a difference between both drugs) regarding macrovascular
complications.

1.1.2 Microvascular complications
Microvascular complications were determined based on the long-term effects on metabolic control. These complications can be subdivided into damage to the eye (retinopathy), kidneys (nephropathy), and nerves (neuropathy). In UKPDS 34, a 25% reduction in microvascular complications was found for intensive T2DM therapy compared to conventional treatment. This was mainly correlated with a good metabolic control (HbA1c) and was not found to be associated to the use of any specific blood glucose lowering medications [16]. Other studies came to similar conclusions, both in type 1 diabetes mellitus and in type 2 diabetes mellitus patients [17-20].

A small scale, crossover study between detemir and glargine (n = 42) in diabetes mellitus type 2 patients with macroangiopathy showed a comparable improvement of parameters of endothelial damage for both drugs [21].

1.1.2.1 Retinopathy
Diabetic retinopathy is the most important cause of blindness. Elderly diabetic patients also have an increased risk of other ocular diseases, such as glaucoma, cataract, and macular degeneration. Regular eye examinations are therefore important [22].

UKPDS 52 investigated the relationship between the severity of retinopathy and the need for photocoagulation after 3, 6 and 9 years of treatment. In patients without retinopathy at baseline, photocoagulation was necessary in 0.2% after 3 years and in 2.6% after 9 years.

The incidence was higher in patients with a microaneurysm at baseline: 0% after 3 years and 4.7% after 9 years. In patients with retinopathy at baseline, photocoagulation was necessary in 15% after 3 years and in 32% after 9 years [23]. UKPDS 50 showed comparable results after a follow-up of 6 years [24].

The UKPDS 33 studies showed significant differences between intensive and conventional treatment groups on a number of individual endpoints associated with diabetic neuropathy, such as photocoagulation of the retina (29% reduction, from 11.0 to 7.9 per 1,000 patient years, p = 0.0031 and cataract extraction (24% reduction, from 7.4 to 5.6 per 1,000 patient years, p = 0.046). No significant differences were seen in blindness or bleeding into the eye [25]. Regarding individual drugs, only glibenclamide showed a significant reduction in the incidence of photocoagulation. No effects of any other individual drug on any parameter were observed. A significant reduction was seen in some ‘surrogateparameters’, like the two-step progression of retinopathy [25].

Glargine has a slightly stronger affinity for IGF-1 receptors than do other insulins, theoretically showing an increased risk of mitogenic activity and an unfavourable effect on the progression of retinopathy. The affinity of glargine to the receptor is however only 0.5% of that of IGF-1 and the greater affinity compared to insulin is only seen at concentrations which are above ‘therapeutic’ concentrations [26]. So far, there are neither epidemiological nor clinical data indicating an unfavourable effect of glargine on retinopathy [27]. All studies with detemir and glargine are of insufficient duration and size to be able to show a relevant effect (let alone a difference between both drugs) regarding retinopathy. In an analysis of four comparative studies no relevant difference was seen between glargine and NPH insulin in the progression of early retinopathy.

1.1.2.2 Nephropathy
The first sign of diabetic nephropathy is microalbuminuria, which is followed by proteinuria. Diabetic nephropathy is one of the most important indications to start haemodialysis. Nephropathy is an important complication of diabetes mellitus. About 25% of type 2 diabetes mellitus patients develop microalbuminuria and 5% of these patients develop macroalbuminuria in 10 years. Only relatively few patients (0.8%) show an increased serum creatinine or need renal function replacement therapy. The latter group however has a considerable increase in disease-related mortality [28].

The UKPDS 33 studies showed no significant differences between intensive and conventional treatments on individual endpoints associated with diabetic nephropathy, such as renal failure or death from renal causes. A significant reduction of microalbuminuria and proteinuria was seen in the intensive group after 9 years of treatment. No effect was seen on creatinine clearance [25].

All studies were of insufficient duration and size to be able to show a relevant effect (let alone a difference between both drugs) regarding nephropathy. No comparative studies between insulins on the effect on nephropathy were identified.

1.1.2.3 Neuropathy
Foot problems are frequently observed as a complication of diabetes, especially in the elderly. Both vascular and neurogenic factors are involved. The prevalence of diabetic neuropathy in patients above 60 years may be over 50%. Diabetic neuropathy is a feared complication of type 2 diabetes mellitus, resulting in paresthesia, burning feeling, or decreased pain sensation, especially in the feet. This may lead to ulceration, infection and gangrene or amputation of the feet [22].

The UKPDS 33 studies showed no significant differences between the intensive and the conventional treatment on individual endpoints associated with diabetic neuropathy, like
amputation [25].

All studies with detemir and glargine were of insufficient duration and size to be able to show a relevant effect (let alone a difference between both drugs) regarding neuropathy.

With respect to macrovascular and microvascular complications, there are no indications of any clinically meaningful differences between degludec, detemir and glargine. All drugs were therefore assigned a value of 50%.

1.2 Effect on metabolic control
The direct effect of insulins can be determined by their effect on glucose concentrations. One study showed a significant reduction of mortality for intensive treatment of diabetes (strict glucose regulation, use of renin-angiotensin inhibitors, aspirin and statins) compared to conventional treatment of diabetes after 13 years of treatment. The relative risk of death was 0.54 in the intensively treated group [29].

Two more recent prospective studies concerning the effects of intensive treatment of diabetes mellitus (target value for HbA1c 6.0%, respectively 6.5%) showed contradictory results. In the ACCORD study (n = 10.251), no significant reduction was seen of important cardiovascular events in the group treated intensively for 3.5 years (HbA1c 6.4%) in comparison with the standard treatment group (HbA1c 7.5%). An increased risk of death was seen in the intensive treatment group (Hazard ratio 1.22. p = 0.04), resulting in premature closure of the study after 3.5 years [30].

In the ADVANCE study (n = 11.140), a significant reduction in the combined endpoint of macrovascular and microvascular complications was seen (Hazard ratio 0.90. p = 0.01) after 5 years of intensive treatment (HbA1c 6.5%), but especially in a reduction of nephropathy (Hazard ratio 0.79. p = 0.006), whereas no significant effect on retinopathy was seen. No increased mortality was seen in this study in the intensively treated group (Hazard ratio 0.93. not significant) [31].

1.3 Relative effects on HbA1c
Insulin therapy is usually titrated until the target HbA1c is reached [2]. Therefore, no substantial differences between insulins are expected.

There are no double-blind studies available that included patients treated with detemir or glargine. All available studies are open label, randomized studies.

Direct comparison between detemir and glargine
One direct comparison study between detemir and glargine, dosed based on the effects on HbA1c, showed (not surprisingly) an identical effect on HbA1c: a decrease of 1.5% compared to baseline. It should be noted that the dosage of detemir (78 IEU) given was higher than that of glargine (44 IU) [32].

In a small-scale crossover study, detemir and glargine showed a similar effect on the 24 h glucose profile [33].

Another study could not demonstrate non-inferiority of detemir compared to glargine. Glargine showed numerically (but not statistically significantly) greater reduction of HbA1c and fasting
blood glucose [34].

A meta-analysis did not show relevant differences between detemir and glargine with respect to efficacy and safety [35].

Direct comparisons between degludec and glargine
Various studies compared glargine to insulin degludec. The effects of both drugs on HbA1c, fasting blood glucose, and body weight were almost identical [36-72]. It should be noted that a recent meta-analysis showed a slight, but statistically significant difference in the effects on HbA1c between glargine and degludec: 0.1% in favour of glargine [73].

Direct comparison between degludec and glargine 300 IU/mL
Some studies compared glargine 300 IU/mL to insulin degludec. The effects of both drugs on HbA1c, fasting blood glucose, and body weight were almost identical [74-78].

Direct comparison between glargine and biosimilar glargine
Biosimilar glargine (LY2963016) was as effective as glargine in several direct comparison studies [79-84].

Direct comparison between glargine 100 IU/mL and 300 IU/mL
Glargine 300 IU/mL was as effective in lowering HbA1c as glargine 100 IU/mL in several direct comparison studies [72, 85-101] and in a meta-analysis [73].

Comparisons with NPH insulin
The effects of detemir and glargine on metabolic control (in comparison with NPH insulin) were investigated in a limited number of studies [102-125]. These studies are included in a number of meta-analyses. The most important conclusions of those meta-analyses are summarized below.

A Cochrane analysis from 2020 included 16 studies with glargine and 8 studies with detemir [126]. In this analysis, only randomized comparative studies between both drugs and NPH insulin were involved with a treatment duration of at least 24 weeks. No significant differences were seen in metabolic control, measured as effect on HbA1c between detemir and NPH insulin and between glargine and NPH insulin. The mean difference in HbA1c for glargine versus NPH was –0.07% (95% CI –0.18 to 0.03; p = 0.17). For insulin detemir compared to NPH insulin, the mean difference was 13% (95% CI –0.02 to 0.28; p = 0.08).

Other comparative studies
Several other studies were performed between the formulations included in this analysis and other blood glucose lowering agents [127-167].

By far the most studies are performed with glargine, whereas fewer studies were done with detemir. Studies comparing two treatment schedules with glargine [168] or non-randomized studies [169], were not included in this analysis. This is also true for similar studies with detemir [170, 171].

In general, glargine has a stronger effect on HbA1c and fasting blood glucose than increasing the dosage of oral antidiabetics or the addition of other blood glucose lowering medicines [134]. Compared to exenatide, a similar effect on HbA1c was seen, but a more marked effect on fasting blood glucose [130, 131, 172]. In comparison with various insulin lispro schedules, a similar or lesser effect on HbA1c was seen, but a stronger effect on fasting blood glucose [135-138].

Comparable insulin requirements were found for both drugs in a double-blind crossover study [139].

An analysis of the German/Austrian DPV-wss database (over 51,000 patients) showed that the mean daily insulin requirements were significantly lower for glargine (0.29 IU/kg) than for detemir (0.33 IU/kg) [144].

The dosage requirements for glargine 300 lU/mL were higher than those for glargine 100 lU/mL (34IU vs 30 IU) after transition to glargine 300 lU/mL [145].

There are no indications of clinically meaningful differences between the insulin analogues, as was expected, because all insulins are normally titrated until the target HbA1c is reached. All drugs score 80%.

2 Safety
Hypoglycaemia is a well-known side effect of insulins. Severe hypoglycaemia is scored under safety (because it may be life threatening), whereas mild cases of hypoglycaemia are scored
under tolerability.

2.1 Risk of severe hypoglycaemia
The most recent Cochrane meta-analyses of the incidence of severe hypoglycaemia showed no significant difference between detemir and glargine on one hand, and NPH insulin on the other, although a trend was observed to a lower incidence for both insulin analogues compared to NPH insulin. Detemir showed a small, but significant reduction of serious hypoglycaemia compared to NPH insulin, which was not demonstrated for glargine, despite the larger number of studies [126]. The incidence is however too low to be considered a significant difference in small-size studies. A trend towards lower incidence was found for detemir (RR 0.50; 95% confidence interval 0.18‒1.38) and glargine (RR 0.70. 95% confidence interval 0.40‒1.23). There are no indications that clinically relevant differences exist between detemir and glargine in the incidence of severe hypoglycaemia. In the direct comparative study between both drugs, an incidence of severe hypoglycaemia of 2% was found for detemir and 3% for glargine [32].

The same is true for the incidence of severe hypoglycaemia for degludec. The number of events was too small to show a significant difference between degludec and glargine [32].

Biosimilar glargine (LY2963016) was as safe as glargine in several direct comparative studies [79-84].

Glargine 300 IU/mL was as safe as glargine in several direct comparative studies with a lower incidence of hypoglycaemia in some studies [86-128].

A meta-analysis showed a lower incidence of severe nocturnal hypoglycaemia for degludec compared to glargine, whereas glargine 300 IU/mL reduced both daytime and nocturnal hypoglycaemia [73].

One real-life, non-comparative, Finnish study showed a lower incidence of severe hypoglycaemia for detemir, but not glargine compared to NPH insulin [173]. Glargine 300 IU/mL and degludec are awarded 80%. Glargine and detemir score 75%.

2.2 Cancer and heart failure
2.2.1 Cancer
There has been debate over whether use of glargine increases the risk of cancer development [174]. However, several studies have now demonstrated that there is no increased risk [175-181]. In addition, no safety signals regarding cancer risk are identified for other insulins.

2.2.2 Heart failure
A comparative study did not show differences between degludec and glargine in the incidence of heart failure [182]. No increased risk of heart failure is identified for detemir. All drugs are awarded 90% for the sub-criterion: cancer/heart failure.

2.3 Documentation
The documentation of the drugs (only comparative studies with more than 25 patients per treatment arm and a treatment duration of at least 10 weeks) is summarized in Table 2.

Table 2 pending to upload

Detemir and glargine are more extensively documented than degludec.

Because of the minor differences between classical glargine (100 U/mL) and the new formulations (300 U/mL) and biosimilar glargine, the clinical experience of glargine was also considered valid for the latter two compounds. The number of available studies was evaluated separately.

3 Tolerability
3.1 Mild to moderate hypoglycaemia
Three meta-analyses showed a significant difference between both insulin analogues and NPH insulin in terms of the incidence of mild to moderate hypoglycaemia and nocturnal hypoglycaemia [126, 183, 184]. The most recent (Cochrane) meta-analysis [126] also showed a lower incidence. The authors found that the relative risk of hypoglycaemia to be glargine 0.88 (95% CI 0.81‒0.96) and detemir 0.73 (95% CI 0.61‒0.86). Also, the risk of nocturnal hypoglycaemia was lower with relative risks: glargine 0.74 (95% CI 0.64‒0.85) and detemir 0.32
(95% CI 0.16‒0.63).

These results should be interpreted with caution. The authors of the analysis make the following remarks:

‘In the studies, very low blood glucose and HbA1c target values were set. However, doctors often recommend higher targets for people with a long history of type 2 diabetes, who have had a heart attack or stroke, or who are old. With higher target values, hypoglycaemia occurs less frequently, and more people need to be treated with insulin analogues instead of NPH insulin to prevent hypoglycaemia in one person. Therefore, study results are only applicable to people who are treated to such low blood glucose target values. In many studies, an adequate adjustment of NPH insulin was not possible. However, doctors will do that in daily practice. Therefore, a further decrease in the benefit of insulin analogues is expected’.

Comparison between detemir and glargine
A meta-analysis did not show relevant differences in hypoglycaemia between detemir and glargine [35].

Comparison between glargine 100 IU/mL and 300 IU/mL
Glargine 300 IU/mL was associated with a lower incidence of nocturnal hypoglycaemia than glargine in several direct comparative studies [86-101].

Comparison between glargine and degludec
Most comparative studies between glargine and insulin degludec showed that degludec exhibited a lower incidence of hypoglycaemia [36-53]. This was also confirmed in several meta-analyses [146-151].

Other comparative studies with glargine and detemir
A planned year one interim analysis of a three-year comparative study of detemir and biphasic insulin twice daily, and short-acting aspart taken three times daily, in insulin-naïve patients who had insufficient control of HbA1c on oral treatment with metformin and/or sulfonylurea derivatives showed significantly less hypoglycaemia with detemir than with the other insulin regimes. Here there were 2 cases per year for detemir vs 8.9 for biphasic insulin and 16 for short-acting insulin. No cases of severe hypoglycaemia were observed [129].

Glargine showed a low incidence of hypoglycaemia in comparative studies with exenatide, oral antidiabetics of various insulin-regimens [130-138].

It should be kept in mind that lower blood glucose and HbA1c target values were set in studies comparing degludec and glargine 300 IU/mL to glargine 100 IU/mL than the values used in daily practice. Therefore, the differences are of limited clinical importance.

Degludec scored 80% because of the relatively low incidence of hypoglycaemia, glargine 300 IU/mL scored 75% and glargine 100 IU/mL and detemir scored 70%.

3.2 Weight increase
The meta-analysis of Monami [183] showed a significantly lower weight increase for detemir compared to NPH insulin, although the absolute difference in weight increase was small (0.7‒2.0 kg). No good explanation is available for this observation. The European Medicines Agency’s European public assessment report (EPAR) of detemir also mentions a lower degree of weight increase for detemir compared to NPH insulin [185].

No differences were seen in the extent of weight increase between glargine and NPH insulin in a meta-analysis [183], nor is this reported in the Scientific Discussion of EMA [186].

The more recent Cochrane meta-analysis showed a non-significant weight increase of 0.12 kg for glargine, compared to NPH insulin. No comparison of detemir and NPH insulin was presented in this study [126].

A direct comparative crossover study between both drugs showed a weight increase of 1.6 kg for glargine, versus a weight loss of 0.4 kg for detemir [21].

In a subsequent randomized study of glargine over time no extra weight increase was seen, with an average 2.1 kg after 1 year treatment and 2.0 kg at the end of 39 months follow-up [187].

In summary, it can be concluded that detemir results in significantly less weight increase compared to NPH insulin, but that the absolute differences are small. This has not been demonstrated for glargine.

Clinical studies show there are no clear differences between degludec and glargine in terms of weight gain in clinical studies.

It is unclear whether there are significant and relevant differences between the medicines on this criterion. Detemir is awarded 80% and glargine and degludec 70%.

3.3 Pain at the injection site
Pain at the injection site is seen more often for detemir than for NPH insulin [188]. This is, to a lesser extent, also the case for glargine compared to NPH insulin [27]. In the direct comparative study between glargine and detemir, a slightly higher incidence of pain was seen for detemir (4.5%) than for glargine (1.4%). Most cases are mild to moderate.

Lipodystrophy can be prevented by frequently changing the site of injection [26].

Studies with degludec are lacking.

Biosimilar glargine (LY2963016) was as well tolerated as glargine in several direct comparative studies [79-82].

Glargine 300 IU/mL was as well tolerated as glargine in several direct comparative studies [86-93].

Glargine is awarded 70% and detemir and degludec 65%.

4 Ease of use
4.1 Dosage frequency
Insulin glargine and degludec can be given once daily. Insulin detemir can be given once or twice daily.

Glargine and degludec are awarded 100% and detemir is awarded 80%.

4.2 Formulations
Both pens and pre-filled injections are available for the drugs.

No independent judgements of the pens or the pre-filled injections are available, so we could not make a distinction between the insulins regarding patient-friendliness and ease of use.

All drugs are awarded 80%.

All insulin analogues are awarded 100%.

5 Applicability
5.1 Interactions
All insulin preparations show the same drug interactions.

Many drug classes may lower or increase insulin need. These will affect the clinical efficacy and safety of detemir or glargine to the same extent.

All drugs are awarded 80%.

5.2 Contra-indications, warnings and monitoring
The drugs are contra-indicated in case of hypersensitivity. There are no indications for relevant differences in the incidence and severity of hypersensitivity reactions for degludec, detemir and
glargine.

This is also true for the warning concerning underdosage (hyperglycaemia) or overdosage (hypoglycaemia). Different doses in IU may be necessary for both drugs during a switch
from NPH insulin.

Detemir contains metacresol which may cause allergic reactions. All drugs are (arbitrarily) awarded 70%.

5.3 Dose adjustments
Insulin needs may be decreased by decreased gluconeogenesis and decreased insulin metabolism. There is no data indicating meaningful differences between degludec, detemir and
glargine.

All drugs are (arbitrarily) awarded 70%.

There do not seem to be relevant differences on this criterion.
All drugs are awarded 80 %.

The SOJA score is presented in Table 3.

Table 3 pending to upload

Discussion

According to the SOJA-matrix, no relevant differences exist between long-acting insulin analogues concerning overall score, with less than 2% difference in score between the highest and lowest scores.

Perhaps this was not surprising, because insulins share many characteristics. This is especially the case for the different formulations of insulin glargine, which are almost identical. Since no clinically relevant differences exist in effectiveness, safety, tolerability, ease of use and applicability, other arguments must determine the preferred use and individual patient characteristics may be decisive.

Applied methodology
The evaluation of the criteria in the SOJA method is highly standardized in order to promote unbiased judgement of drugs from various drug groups based on clinically relevant criteria. The essence of the SOJA method is that users of the method may assign their own relative weight to each selection criterion. This interactive programme is available on the Internet: www.tablet. sojaonline.nl. It is not likely that major differences between the insulin analogues in scores will result in different weightings of the selection criteria. The SOJA method is intended as a tool for rational drug decision-making, forcing clinicians and pharmacists to include all relevant aspects of a certain group of drugs, thereby preventing formulary decisions being based on only one or two criteria. Besides this, possible ‘hidden criteria’ are excluded from the decision-making process.

There will of course always be room for debate whether or not the correct scoring system was used for each criterion and judgement may be arbitrary for most, if not all, criteria. In this analysis, the weights of the different categories and scores assigned to the different insulins were based on consensus between the authors. The outcome of this study should be seen as the basis for discussions within formulary committees and not as the absolute truth.

Outcomes
Minimal differences in score are seen between the insulin analogues (less than 2% between the highest and lowest score). Therefore, no relevant differences were found between the long-acting insulin analogues. The situation may be different in individual patients. When an individual patient shows (severe) hypoglycaemia, degludec or glargine 300 IU/mL may offer advantages over glargine 100 IU/mL. As mentioned above, in spite of the standardized method, the scoring will always depend on the somewhat subjective judgement of the scores. Since the differences in the properties of the insulins are so limited, it seems quite unlikely that assigning other relative weights and or scores to the selection criteria will result in meaningful differences in the scores.

Selection criteria
Clinical efficacy and safety are the most important selection criteria for all groups of medicines. Meta-analyses and registry data may be of value in the judgement of efficacy and safety. All data sources have specific strengths and weaknesses.

Acquisition cost was not included as a selection criterion to make the score internationally applicable. The present matrix can be used as a pre-selection tool of the most suitable long-acting insulin analogues from a product specific quality point of view. Because prices may differ between institutions and in different healthcare systems, individual procurement procedures should lead to a selection of the most cost-effective options. Glargine 100 IU/mL (biosimilar or originator) is the cheapest option in most cases.

We did not include NPH insulin in this score, because this analysis was limited to long-acting insulin analogues. If NPH insulin would have been included, it would score similar to the analogues on most selection criteria. It would score slightly lower than glargine 100 IU/mL and detemir for safety and tolerability because of the higher incidence of hypoglycaemia.

Nevertheless, it should not be overlooked that ‘good old’ NPH insulin is still a good option, also from a formulary perspective. NPH insulin is likely to be cheaper than biosimilar glargine in most countries.

Conclusions

We found almost identical scores for the long-acting insulin analogues. Therefore, acquisition cost and individual patient characteristics may determine the choice from a formulary perspective. Glargine 100 IU/mL (biosimilar or originator) is the cheapest option in most cases.

Competing interests: None to declare for both authors.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Robert Janknegt, PharmD, PhD, Hospital Pharmacist, Clinical Pharmacologist, Sittard-Geleen, The Netherlands

Marloes Dankers, MSc, Pharmacist, Institute for the Rational Use of Medicine, The Netherlands

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Author for correspondence: Lyndsay Davies, PhD, Senior Pharmaceutical Biochemistry Analyst, Quality Control North West – Liverpool, Pharmacy Practice Unit, 70 Pembroke Place, Liverpool L69 3GF, UK

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