Review
New forms of insulin and insulin therapies for the treatment of type 2 diabetes Avivit Cahn, Roberto Miccoli, Angela Dardano, Stefano Del Prato*
Insulin is a common treatment option for many patients with type 2 diabetes, and is generally used late in the natural history of the disease. Its injectable delivery mode, propensity for weight gain and hypoglycaemia, and the paucity of trials assessing the risk-to-safety ratio of early insulin use are major shortcomings associated with its use in patients with type 2 diabetes. Development of new insulins—such as insulin analogues, including long-acting and shortacting insulins—now provide alternative treatment options to human insulin. These novel insulin formulations and innovative insulin delivery methods, such as oral or inhaled insulin, have been developed with the aim to reduce insulin-associated hypoglycaemia, lower intraindividual pharmacokinetic and pharmacodynamic variability, and improve imitation of physiological insulin release. Availability of newer glucose-lowering drugs (such as glucagonlike peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors) also offers the opportunity for combination treatment; the results of the first trials in this area of research suggest that such treatment might lead to use of reduced insulin doses, less weight gain, and fewer hypoglycaemic episodes than insulin treatment alone. These and future developments will hopefully offer better opportunities for individualisation of insulin treatment for patients with type 2 diabetes.
Lancet Diabetes Endocrinol 2015
Introduction
Correspondence to: Prof Stefano Del Prato, Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa, 56124 Pisa, Italy [email protected]
Insulin remains the cornerstone of diabetes treatment. More than 90 years of clinical data support use of this hormone, and it is still the most effective treatment to reduce glucose and HbA1c concentrations, even with the emergence of many new drug classes for diabetes treatment. In autoimmune type 1 diabetes, insulin is the sole treatment and has been used to save millions of lives since its discovery. In people with type 2 diabetes, insulin can be prescribed as a first-line treatment for those intolerant to other antidiabetes drugs, in the presence of advanced renal or hepatic failure, or in individuals with a primary β-cell defect—such as those with latent autoimmune diabetes of the adult (panel). Moreover, although many other pharmacological drugs are now available, insulin is still recommended as the preferred, if not the only, treatment for patients with type 2 diabetes who are not at the target HbA1c despite lifestyle changes and maximum dose of non-insulin treatment.1–4 During the past decades many manipulations of the insulin molecule have attempted to provide an increasingly effective and safe treatment option for patients. Development of insulin treatment has given rise to longacting and short-acting insulin analogues as alternatives to human insulin. These and emerging insulin preparations, and the availability of novel antihyperglycaemic drugs that can be combined with insulin, provide opportunities for treatment that are thought to reduce side-effects of insulin treatment and address the many pathogenetic mechanisms in type 2 diabetes. In this Review, we discuss new and emerging insulin formulations as well as strategies of insulin administration and their potential as treatments for people with type 2 diabetes. We also review evidence for combining insulin therapy with new non-insulin hypoglycaemic drugs and, finally, discuss intensification of insulin treatment with existing and emerging forms of insulin.
The present role of insulin in type 2 diabetes treatment Type 2 diabetes is characterised by progressive deterioration of glycaemic control. Early intervention and maintenance of good glycaemic control from the time of diagnosis is strongly recommended in treatment guidelines1–4 because it is the most effective way to reduce the burden of longterm complications.5–8 However, to achieve glycaemic targets is a challenge for both patients and health-care
Published Online June 5, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00097-2 Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel (A Cahn MD); and Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa, Pisa, Italy (R Miccoli MD, A Dardano MD, Prof S Del Prato MD)
Panel: Indications for insulin treatment in patients with type 2 diabetes Strong indications • New diagnosis or long-term diabetes with symptoms of hyperglycaemia (rescue treatment) • Ketoacidosis • Non-insulin hypoglycaemic treatments not tolerated or contraindicated • Acute medical events (eg, infection or myocardial infarction) or major surgery • Concomitant disease such as pancreatitis, cirrhosis, or chronic steroid treatment • Failure of non-insulin treatments (replacement treatment) Potential indications • Glycaemic control not achieved with diet, exercise, non-insulin drugs (augmentation treatment), and latent autoimmune diabetes • Women with diabetes who are pregnant or planning a pregnancy • Patients admitted to hospital and unable to take their usual drug regimen or during enteral or parenteral nutrition • Increasingly flexible lifestyle or unplanned eating behaviour (older patients)
www.thelancet.com/diabetes-endocrinology Published online June 5, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00097-2
1
Review
providers (figure 1). Oral hypoglycaemic agents (OHA) alone are frequently insufficient for maintenance of glycaemic control,10 and with the progressive loss of β-cell function that is characteristic of the disease11 treatment (including insulin therapy) might need to be intensified. In the UKPDS study,12 more than half of the participants with newly diagnosed type 2 diabetes and initially started on OHA needed additional insulin therapy within 6 years. Another study13 reported that 25% of patients with type 2 diabetes were given a prescription of insulin within 6 years after initiating OHA treatment, increasing to 42% after 10 years. This progressive increase shows either difficulties in ensuring adequate glycaemic control or need to intensify treatment to meet patients’ glycaemic targets, which is an attempt to reduce the risk of diabetic complications. Yet, reservation still exists with respect to timely initiation of insulin therapy. The A1chieve study14 was a noninterventional 6 month study, including 66 726 patients with type 2 diabetes. Participants were both insulin (32·8%) and non-insulin (67·2%) users, had a mean duration of diabetes of 8 years at baseline, and mean HbA1c of 9·5% (SD 1·7) and 9·4% (1·8), respectively;14 30–90% of these patients had diabetic complications.15 This observation suggests that insufficient intensification of treatment, including delayed introduction of insulin therapy and ineffective insulin treatment, leads to poor glycaemic control and increased risk of complications. Therefore the question arises as to why insulin therapy is often delayed and, if initiated, why it is not always effective. The major reservations expressed by both
90
Health-care professionals Patients who are insulin naive
80
Respondents (%)
70 60 50 40 30 20 10 0
Insulin causes weight gain
Fear of hypoglycaemia
Pain from injection
Pain from blood tests
Possible reasons given to not use insulin treatment
Figure 1: Reasons why health-care professionals and patients might refrain from starting insulin treatment Results from a case-control descriptive study9 of 92 patients with diabetes who needed initiation of insulin treatment because of failure (HbA1c >8·5%) on maximum oral drugs. Participants were interviewed about attitudes and thoughts regarding their illness and insulin treatment, and 157 family physicians completed a questionnaire regarding barriers to insulin treatment and answered an open-ended question about the criteria for starting insulin treatment. Figure is adapted from Nakar and colleagues,9 by permission of Elsevier.
2
patients and physicians include fear of hypoglycaemia, concern for the often accompanying weight gain, the psychological stigma of initiating insulin therapy, inconvenience of injections, and need for qualified staff to instruct the patient about the use of insulin and its titration (figure 1).9 These factors, the appropriate selection of patients with type 2 diabetes for insulin therapy, and the timing of insulin initiation have been reviewed elsewhere16 and will not be covered in depth in this Review. Among other concerns, long-term safety remains a factor limiting the initiation and intensification of insulin treatment.17 Despite insulin being used for almost a century for treatment of diabetes, few trials allow for the definition of a proper risk-to-safety ratio of insulin use in patients with type 2 diabetes.18 Many attitudes and suggestions about timely initiation of insulin treatment are based on a wide range of opinions rather than trial-generated evidence.16 A 3·3 year retrospective study,19 including 6484 people with type 2 diabetes who were progressing to treatment with insulin monotherapy, showed an association between insulin treatment and insulin dose and increased risk of allcause mortality, major adverse cardiovascular events, and cancer. However, the retrospective aspect of the study calls for more specific intervention trials. Of the few published studies into this topic, the ORIGIN trial20 showed that use of insulin glargine to target normal fasting plasma glucose in people with type 2 diabetes and cardiovascular disease or cardiovascular risk factors, or those with impaired glucose tolerance and impaired fasting glucose, had a neutral effect on cardiovascular outcomes (hazard ratio 1·02, 95% CI 0·94–1·11, p=0·63) and cancer (1·00, 0·88–1·13, p=0·97). However, in this trial20 quite a low insulin dose was used compared with the higher insulin needed in patients with advanced stages of the disease, a fact to be taken into consideration in view of the dose–effect association between insulin and cardiovascular risk reported in retrospective analyses.19 Data from ORIGIN20 and UKPDS follow-up21 suggest that insulin treatment could be safe when introduced early in the disease course. By contrast, data from other studies suggest that intensive insulin treatment in patients with type 2 diabetes with more advanced stage and with overt complications (as those recruited in the trials ACCORD22 and VADT23) might increase the cardiovascular risk and all-cause mortality. Thus, appropriate use of insulin treatment needs better characterisation of the heterogeneity of the disease noted in participants with type 2 diabetes. Therefore, to decide when to initiate insulin and select an insulin treatment regimen, several elements should be considered,16 including actual and biological age, initial bodyweight, implications of future bodyweight gain, and presence of comorbidities—such as cardiovascular disease, renal insufficiency, impaired cognitive function, and visual impairment. Additional factors are the propensity to develop hypoglycaemia and impaired ability to recognise
www.thelancet.com/diabetes-endocrinology Published online June 5, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00097-2
Review
hypoglycaemic symptoms. Finally, personal needs have to be considered, such as acceptance of injections and willingness to monitor blood glucose, special requirements associated with jobs and leisure activities, and capacity of self-management. Accurate education and empowerment of patients are necessary to cope with some of these aspects, but pharmacological technology might also contribute to make future insulin treatment easier, more acceptable, and, possibly, more effective with fewer drawbacks. Recent developments have attempted to address some of these drawbacks. Both weight gain and hypoglycaemia stem from the inability of the exogenously delivered insulin to mimic the physiological profile of insulin secretion. Novel insulin formulations and innovative insulin delivery methods should ensure a more physiological daily insulin profile and, thereby, decrease the risk of hypoglycaemia and the propensity for weight gain. Additionally, alternative routes of insulin administration can alleviate patients’ needle phobia. Finally, combination of insulin with insulin sensitisers or novel antihyperglycaemic drugs might reduce insulin dose needed, occasionally resulting in lower risk of hypoglycaemia and less weight gain or even weight loss. However, whether these innovations could also alleviate long-term concerns so far related to classic insulin treatment needs careful surveillance and planned trials.
New insulin formulations Long-acting analogues Basal insulin is regarded as the optimum choice for most individuals with type 2 diabetes starting insulin treatment (table 1).4 Generally injected at bedtime, basal insulin suppresses overnight hepatic glucose production and ensures better fasting plasma concentrations of glucose.24 Introduction of long-acting insulin analogues (ie, insulin glargine and insulin detemir) has been welcomed as an opportunity to achieve better glycaemic control with fewer side-effects than with neutral protamine hagedorn (NPH) insulin. Modification of the pharmacokinetics and pharmacodynamics of basal insulin results in flatter plasma insulin concentrations upon injection, better dayto-day reproducibility, and reduced risk of nocturnal hypoglycaemia.25 To further improve these features, new insulin formulations have been synthesised to extend their time–action profile to be longer than 24 h. Although these long-acting analogues offer the initial promise of less than once daily administration, no insulin formulation has achieved this goal. Degludec is a desB30 insulin acylated at the LysB29 residue with a glutamate linker and a hexadecandioyl fatty acid side chain,26 which was approved for licensing by the European Medicines Agency whereas the US Food and Drug Administration (FDA) has requested a cardiovascular safety trial before making any further decisions. Degludec shows an insulin-receptor binding specificity and a metabolic-to-mitogenic ratio that is
Time for onset of action
Time until peak action
Duration of action
Rapid-acting insulins Regular human insulin
30–60 min
Aspart
12–18 min
30–90 min
2–4 h
5–8 h 3–5 h
Glulisine
12–30 min
30–90 min
3–5 h
Lispro
15–30 min
30–90 min
3–5 h
Intermediate-acting analogues NPH Lispro protamine
1–2 h 30–60 min
4–12 h
12–16 h
4–12 h
12–16 h
Long-acting analogues Detemir
1–2 h
Glargine
1–2 h
None
20–26 h
1–2 h
None
up to 36 h
None
>42 h
Glargine U300 Degludec
30–90 min
6–8 h
up to 24 h
Pre-mixed 70% NPH, 30% regular
30–60 min
2–4 h
10–16 h
50% NPH, 50% regular
30–60 min
2–5 h
10–16 h
30% aspart protamine, 70% aspart
5–15 min
1–4 h
10–16 h
50% aspart protamine, 50% aspart
15–30 min
1–4 h
10–16 h
70% aspart protamine, 30% aspart
15–30 min
1–12 h
10–16 h
50% lispro protamine, 50% lispro
10–15 min
1–4 h
10–16 h
75% lispro protamine, 25% lispro
10–15 min
1–12 h
10–16 h
NPH=neutral protamine hagedorn.
Table 1: Pharmacokinetics of available insulin formulations
comparable with that of human insulin.27 Its mean halflife is 24·5 h and its metabolic effect is still apparent 42 h after injection.28 In a pre-planned meta-analysis of phase 3 studies,29 which included 5299 people with type 2 diabetes, use of insulin degludec was associated with a significantly lower rate of overall confirmed and nocturnal episodes of hypoglycaemia than with insulin glargine (relative risk 0·83, [95% CI 0·74–0·94] and 0·68 [0·57–0·82], respectively). Whether this difference translates into clinical benefits in real-life settings, however, needs extensive assessment. On the basis of a study30 published in 2014, one patient needs to be treated for 4 months with insulin degludec versus glargine to avoid one confirmed hypoglycaemic episode, and two patients need to be treated for 1 year to avoid one nocturnal confirmed hypoglycaemic episode. Moreover, the cost-effectiveness for the use of degludec versus glargine in patients with type 2 diabetes has not yet been extensively assessed; however, analyses done on the basis of data generated by the phase 3 studies have shown that insulin degludec is a cost-effective treatment compared with glargine and offers additional benefits for people with type 2 diabetes and recurrent hypoglycaemia.31 Although insulin degludec is the latest long-acting insulin analogue to be approved, other long-acting insulin formulations are being developed. PEGylated insulin (LY2605541), which consists of insulin lispro with a covalently bound polyethylene glycol moiety at lysine B28,31 slows the absorption of insulin from the injection
www.thelancet.com/diabetes-endocrinology Published online June 5, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00097-2
3
Review
site and reduces renal insulin clearance, resulting in a half-life as long as 75 h with a flat time–action profile.32 Initial results from phase 3 studies comparing it with insulin glargine reported similar efficacy in terms of HbA1c reduction. Use of PEGylated insulin was associated with a lower risk of hypoglycaemia and less apparent increase in bodyweight than with insulin glargine,33 but results from larger and longer-term studies are needed before crucial comparison with existing long-acting insulin analogues is possible. Glargine U300 is a new, more concentrated (300 U/mL), formulation than insulin glargine U100 with no other molecular changes. This new formulation was approved in the beginning of 2015 for market use by the FDA34 and the European Medicines Agency.35 Upon injection, glargine U300 forms a compact subcutaneous depot with a small surface area that results in a more gradual, long-term, and flatter release than with standard glargine, enabling glucose control for up to 36 h. Glargine U300 has been compared with insulin glargine in clinical trials of patients with type 2 diabetes who were given basal-bolus insulin or basal insulin plus OHAs.36–38 Basal insulin doses were titrated to target a similar fasting plasma glucose (4·4–5·6 mmol/L). After 6 months of treatment, HbA1c reduction was equivalent between regimens, although use of glargine U300 was associated with fewer instances of nocturnal confirmed hypoglycaemia (≤70 mg/dL) or severe hypoglycaemia.36–38 Thus far, the ultra-long pharmacokinetic profile of the novel, long-acting insulin analogues provides the clinical benefit of reduced cases of nocturnal hypoglycaemia. Whether the use of these and other insulins in development with increasingly long and flat profiles will lead to improved glycaemic control has yet to be shown. Moreover, possible benefits of the novel analogues will still need to be balanced by long-term safety and efficacy data.
Rapid-acting analogues Although basal insulin is preferred for initiation of insulin treatment in patients with type 2 diabetes, many individuals then later advance to a disease stage when prandial insulin is necessary. Rapid-acting insulin analogues were introduced to the market in the mid1990s and have undergone continuous developments (table 2). These analogues have a faster onset and shorter duration of action than human insulin and provide more control of post prandial glucose than does human insulin, with no significant difference in the risk of hypoglycaemia.39 However, the pharmacokinetic profile of rapid-acting insulins is far from ideal because they only estimate the pattern of physiological insulin release. In particular, these insulin analogues cannot fully reproduce the prompt increase in circulating insulin upon ingestion of a meal. In the past decade, several attempts have been made to develop ultra-rapid-acting insulins, many of which have focused on conjugation with excipients or enzymes that accelerate absorption of 4
insulin monomers, whereas other approaches have attempted to change insulin pharmacokinetics by affecting route of delivery (table 2). Changes in the formulation of subcutaneously injected insulin to increase insulin absorption rate has been attempted by different manipulations. Addition of edetic acid, a chelator of zinc, to the insulin hexamer (BioD-090, VIAject; Biodel Inc, Danbury, CT, USA)40 causes a more rapid dissociation of the hexamer into dimers and monomers when subcutaneously injected, resulting in a faster maximum glucose-lowering effect. Overall experience of rapid-acting analogues in patients with type 2 diabetes is small and very rare. In 14 patients with type 2 diabetes, a single dose of BioD-090, human regular insulin, or insulin lispro before a test of a standardised liquid meal was associated with comparable absolute plasma glucose concentrations and similar timecourse of plasma glucose concentrations between insulin types.41 Injection of a rapid-acting insulin with recombinant human hyaluronidase (rHuPH20)42 leads to disruption of the hyaluronic acid in the subcutaneous adipose layer, enabling a more rapid spread of the locally injected insulin, and better absorption than rapid-acting insulins without rHuPH20. In a trial including 21 patients with type 2 diabetes, use of insulin lispro with rHuPH20 provided better control of glycaemic excursion than with lispro alone, with lower insulin requirements and lower hypoglycaemic excursion, as indicated by an improvement of both hyperglycaemic (area under the curve [AUC]0–4h >7·8 mmol/L, 56% of control, p=0·48) and hypoglycaemic (AUC0–8 h
New forms of insulin and insulin therapies for the treatment of type 2 diabetes Avivit Cahn, Roberto Miccoli, Angela Dardano, Stefano Del Prato*
Insulin is a common treatment option for many patients with type 2 diabetes, and is generally used late in the natural history of the disease. Its injectable delivery mode, propensity for weight gain and hypoglycaemia, and the paucity of trials assessing the risk-to-safety ratio of early insulin use are major shortcomings associated with its use in patients with type 2 diabetes. Development of new insulins—such as insulin analogues, including long-acting and shortacting insulins—now provide alternative treatment options to human insulin. These novel insulin formulations and innovative insulin delivery methods, such as oral or inhaled insulin, have been developed with the aim to reduce insulin-associated hypoglycaemia, lower intraindividual pharmacokinetic and pharmacodynamic variability, and improve imitation of physiological insulin release. Availability of newer glucose-lowering drugs (such as glucagonlike peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors) also offers the opportunity for combination treatment; the results of the first trials in this area of research suggest that such treatment might lead to use of reduced insulin doses, less weight gain, and fewer hypoglycaemic episodes than insulin treatment alone. These and future developments will hopefully offer better opportunities for individualisation of insulin treatment for patients with type 2 diabetes.
Lancet Diabetes Endocrinol 2015
Introduction
Correspondence to: Prof Stefano Del Prato, Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa, 56124 Pisa, Italy [email protected]
Insulin remains the cornerstone of diabetes treatment. More than 90 years of clinical data support use of this hormone, and it is still the most effective treatment to reduce glucose and HbA1c concentrations, even with the emergence of many new drug classes for diabetes treatment. In autoimmune type 1 diabetes, insulin is the sole treatment and has been used to save millions of lives since its discovery. In people with type 2 diabetes, insulin can be prescribed as a first-line treatment for those intolerant to other antidiabetes drugs, in the presence of advanced renal or hepatic failure, or in individuals with a primary β-cell defect—such as those with latent autoimmune diabetes of the adult (panel). Moreover, although many other pharmacological drugs are now available, insulin is still recommended as the preferred, if not the only, treatment for patients with type 2 diabetes who are not at the target HbA1c despite lifestyle changes and maximum dose of non-insulin treatment.1–4 During the past decades many manipulations of the insulin molecule have attempted to provide an increasingly effective and safe treatment option for patients. Development of insulin treatment has given rise to longacting and short-acting insulin analogues as alternatives to human insulin. These and emerging insulin preparations, and the availability of novel antihyperglycaemic drugs that can be combined with insulin, provide opportunities for treatment that are thought to reduce side-effects of insulin treatment and address the many pathogenetic mechanisms in type 2 diabetes. In this Review, we discuss new and emerging insulin formulations as well as strategies of insulin administration and their potential as treatments for people with type 2 diabetes. We also review evidence for combining insulin therapy with new non-insulin hypoglycaemic drugs and, finally, discuss intensification of insulin treatment with existing and emerging forms of insulin.
The present role of insulin in type 2 diabetes treatment Type 2 diabetes is characterised by progressive deterioration of glycaemic control. Early intervention and maintenance of good glycaemic control from the time of diagnosis is strongly recommended in treatment guidelines1–4 because it is the most effective way to reduce the burden of longterm complications.5–8 However, to achieve glycaemic targets is a challenge for both patients and health-care
Published Online June 5, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00097-2 Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel (A Cahn MD); and Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, University of Pisa, Pisa, Italy (R Miccoli MD, A Dardano MD, Prof S Del Prato MD)
Panel: Indications for insulin treatment in patients with type 2 diabetes Strong indications • New diagnosis or long-term diabetes with symptoms of hyperglycaemia (rescue treatment) • Ketoacidosis • Non-insulin hypoglycaemic treatments not tolerated or contraindicated • Acute medical events (eg, infection or myocardial infarction) or major surgery • Concomitant disease such as pancreatitis, cirrhosis, or chronic steroid treatment • Failure of non-insulin treatments (replacement treatment) Potential indications • Glycaemic control not achieved with diet, exercise, non-insulin drugs (augmentation treatment), and latent autoimmune diabetes • Women with diabetes who are pregnant or planning a pregnancy • Patients admitted to hospital and unable to take their usual drug regimen or during enteral or parenteral nutrition • Increasingly flexible lifestyle or unplanned eating behaviour (older patients)
www.thelancet.com/diabetes-endocrinology Published online June 5, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00097-2
1
Review
providers (figure 1). Oral hypoglycaemic agents (OHA) alone are frequently insufficient for maintenance of glycaemic control,10 and with the progressive loss of β-cell function that is characteristic of the disease11 treatment (including insulin therapy) might need to be intensified. In the UKPDS study,12 more than half of the participants with newly diagnosed type 2 diabetes and initially started on OHA needed additional insulin therapy within 6 years. Another study13 reported that 25% of patients with type 2 diabetes were given a prescription of insulin within 6 years after initiating OHA treatment, increasing to 42% after 10 years. This progressive increase shows either difficulties in ensuring adequate glycaemic control or need to intensify treatment to meet patients’ glycaemic targets, which is an attempt to reduce the risk of diabetic complications. Yet, reservation still exists with respect to timely initiation of insulin therapy. The A1chieve study14 was a noninterventional 6 month study, including 66 726 patients with type 2 diabetes. Participants were both insulin (32·8%) and non-insulin (67·2%) users, had a mean duration of diabetes of 8 years at baseline, and mean HbA1c of 9·5% (SD 1·7) and 9·4% (1·8), respectively;14 30–90% of these patients had diabetic complications.15 This observation suggests that insufficient intensification of treatment, including delayed introduction of insulin therapy and ineffective insulin treatment, leads to poor glycaemic control and increased risk of complications. Therefore the question arises as to why insulin therapy is often delayed and, if initiated, why it is not always effective. The major reservations expressed by both
90
Health-care professionals Patients who are insulin naive
80
Respondents (%)
70 60 50 40 30 20 10 0
Insulin causes weight gain
Fear of hypoglycaemia
Pain from injection
Pain from blood tests
Possible reasons given to not use insulin treatment
Figure 1: Reasons why health-care professionals and patients might refrain from starting insulin treatment Results from a case-control descriptive study9 of 92 patients with diabetes who needed initiation of insulin treatment because of failure (HbA1c >8·5%) on maximum oral drugs. Participants were interviewed about attitudes and thoughts regarding their illness and insulin treatment, and 157 family physicians completed a questionnaire regarding barriers to insulin treatment and answered an open-ended question about the criteria for starting insulin treatment. Figure is adapted from Nakar and colleagues,9 by permission of Elsevier.
2
patients and physicians include fear of hypoglycaemia, concern for the often accompanying weight gain, the psychological stigma of initiating insulin therapy, inconvenience of injections, and need for qualified staff to instruct the patient about the use of insulin and its titration (figure 1).9 These factors, the appropriate selection of patients with type 2 diabetes for insulin therapy, and the timing of insulin initiation have been reviewed elsewhere16 and will not be covered in depth in this Review. Among other concerns, long-term safety remains a factor limiting the initiation and intensification of insulin treatment.17 Despite insulin being used for almost a century for treatment of diabetes, few trials allow for the definition of a proper risk-to-safety ratio of insulin use in patients with type 2 diabetes.18 Many attitudes and suggestions about timely initiation of insulin treatment are based on a wide range of opinions rather than trial-generated evidence.16 A 3·3 year retrospective study,19 including 6484 people with type 2 diabetes who were progressing to treatment with insulin monotherapy, showed an association between insulin treatment and insulin dose and increased risk of allcause mortality, major adverse cardiovascular events, and cancer. However, the retrospective aspect of the study calls for more specific intervention trials. Of the few published studies into this topic, the ORIGIN trial20 showed that use of insulin glargine to target normal fasting plasma glucose in people with type 2 diabetes and cardiovascular disease or cardiovascular risk factors, or those with impaired glucose tolerance and impaired fasting glucose, had a neutral effect on cardiovascular outcomes (hazard ratio 1·02, 95% CI 0·94–1·11, p=0·63) and cancer (1·00, 0·88–1·13, p=0·97). However, in this trial20 quite a low insulin dose was used compared with the higher insulin needed in patients with advanced stages of the disease, a fact to be taken into consideration in view of the dose–effect association between insulin and cardiovascular risk reported in retrospective analyses.19 Data from ORIGIN20 and UKPDS follow-up21 suggest that insulin treatment could be safe when introduced early in the disease course. By contrast, data from other studies suggest that intensive insulin treatment in patients with type 2 diabetes with more advanced stage and with overt complications (as those recruited in the trials ACCORD22 and VADT23) might increase the cardiovascular risk and all-cause mortality. Thus, appropriate use of insulin treatment needs better characterisation of the heterogeneity of the disease noted in participants with type 2 diabetes. Therefore, to decide when to initiate insulin and select an insulin treatment regimen, several elements should be considered,16 including actual and biological age, initial bodyweight, implications of future bodyweight gain, and presence of comorbidities—such as cardiovascular disease, renal insufficiency, impaired cognitive function, and visual impairment. Additional factors are the propensity to develop hypoglycaemia and impaired ability to recognise
www.thelancet.com/diabetes-endocrinology Published online June 5, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00097-2
Review
hypoglycaemic symptoms. Finally, personal needs have to be considered, such as acceptance of injections and willingness to monitor blood glucose, special requirements associated with jobs and leisure activities, and capacity of self-management. Accurate education and empowerment of patients are necessary to cope with some of these aspects, but pharmacological technology might also contribute to make future insulin treatment easier, more acceptable, and, possibly, more effective with fewer drawbacks. Recent developments have attempted to address some of these drawbacks. Both weight gain and hypoglycaemia stem from the inability of the exogenously delivered insulin to mimic the physiological profile of insulin secretion. Novel insulin formulations and innovative insulin delivery methods should ensure a more physiological daily insulin profile and, thereby, decrease the risk of hypoglycaemia and the propensity for weight gain. Additionally, alternative routes of insulin administration can alleviate patients’ needle phobia. Finally, combination of insulin with insulin sensitisers or novel antihyperglycaemic drugs might reduce insulin dose needed, occasionally resulting in lower risk of hypoglycaemia and less weight gain or even weight loss. However, whether these innovations could also alleviate long-term concerns so far related to classic insulin treatment needs careful surveillance and planned trials.
New insulin formulations Long-acting analogues Basal insulin is regarded as the optimum choice for most individuals with type 2 diabetes starting insulin treatment (table 1).4 Generally injected at bedtime, basal insulin suppresses overnight hepatic glucose production and ensures better fasting plasma concentrations of glucose.24 Introduction of long-acting insulin analogues (ie, insulin glargine and insulin detemir) has been welcomed as an opportunity to achieve better glycaemic control with fewer side-effects than with neutral protamine hagedorn (NPH) insulin. Modification of the pharmacokinetics and pharmacodynamics of basal insulin results in flatter plasma insulin concentrations upon injection, better dayto-day reproducibility, and reduced risk of nocturnal hypoglycaemia.25 To further improve these features, new insulin formulations have been synthesised to extend their time–action profile to be longer than 24 h. Although these long-acting analogues offer the initial promise of less than once daily administration, no insulin formulation has achieved this goal. Degludec is a desB30 insulin acylated at the LysB29 residue with a glutamate linker and a hexadecandioyl fatty acid side chain,26 which was approved for licensing by the European Medicines Agency whereas the US Food and Drug Administration (FDA) has requested a cardiovascular safety trial before making any further decisions. Degludec shows an insulin-receptor binding specificity and a metabolic-to-mitogenic ratio that is
Time for onset of action
Time until peak action
Duration of action
Rapid-acting insulins Regular human insulin
30–60 min
Aspart
12–18 min
30–90 min
2–4 h
5–8 h 3–5 h
Glulisine
12–30 min
30–90 min
3–5 h
Lispro
15–30 min
30–90 min
3–5 h
Intermediate-acting analogues NPH Lispro protamine
1–2 h 30–60 min
4–12 h
12–16 h
4–12 h
12–16 h
Long-acting analogues Detemir
1–2 h
Glargine
1–2 h
None
20–26 h
1–2 h
None
up to 36 h
None
>42 h
Glargine U300 Degludec
30–90 min
6–8 h
up to 24 h
Pre-mixed 70% NPH, 30% regular
30–60 min
2–4 h
10–16 h
50% NPH, 50% regular
30–60 min
2–5 h
10–16 h
30% aspart protamine, 70% aspart
5–15 min
1–4 h
10–16 h
50% aspart protamine, 50% aspart
15–30 min
1–4 h
10–16 h
70% aspart protamine, 30% aspart
15–30 min
1–12 h
10–16 h
50% lispro protamine, 50% lispro
10–15 min
1–4 h
10–16 h
75% lispro protamine, 25% lispro
10–15 min
1–12 h
10–16 h
NPH=neutral protamine hagedorn.
Table 1: Pharmacokinetics of available insulin formulations
comparable with that of human insulin.27 Its mean halflife is 24·5 h and its metabolic effect is still apparent 42 h after injection.28 In a pre-planned meta-analysis of phase 3 studies,29 which included 5299 people with type 2 diabetes, use of insulin degludec was associated with a significantly lower rate of overall confirmed and nocturnal episodes of hypoglycaemia than with insulin glargine (relative risk 0·83, [95% CI 0·74–0·94] and 0·68 [0·57–0·82], respectively). Whether this difference translates into clinical benefits in real-life settings, however, needs extensive assessment. On the basis of a study30 published in 2014, one patient needs to be treated for 4 months with insulin degludec versus glargine to avoid one confirmed hypoglycaemic episode, and two patients need to be treated for 1 year to avoid one nocturnal confirmed hypoglycaemic episode. Moreover, the cost-effectiveness for the use of degludec versus glargine in patients with type 2 diabetes has not yet been extensively assessed; however, analyses done on the basis of data generated by the phase 3 studies have shown that insulin degludec is a cost-effective treatment compared with glargine and offers additional benefits for people with type 2 diabetes and recurrent hypoglycaemia.31 Although insulin degludec is the latest long-acting insulin analogue to be approved, other long-acting insulin formulations are being developed. PEGylated insulin (LY2605541), which consists of insulin lispro with a covalently bound polyethylene glycol moiety at lysine B28,31 slows the absorption of insulin from the injection
www.thelancet.com/diabetes-endocrinology Published online June 5, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00097-2
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site and reduces renal insulin clearance, resulting in a half-life as long as 75 h with a flat time–action profile.32 Initial results from phase 3 studies comparing it with insulin glargine reported similar efficacy in terms of HbA1c reduction. Use of PEGylated insulin was associated with a lower risk of hypoglycaemia and less apparent increase in bodyweight than with insulin glargine,33 but results from larger and longer-term studies are needed before crucial comparison with existing long-acting insulin analogues is possible. Glargine U300 is a new, more concentrated (300 U/mL), formulation than insulin glargine U100 with no other molecular changes. This new formulation was approved in the beginning of 2015 for market use by the FDA34 and the European Medicines Agency.35 Upon injection, glargine U300 forms a compact subcutaneous depot with a small surface area that results in a more gradual, long-term, and flatter release than with standard glargine, enabling glucose control for up to 36 h. Glargine U300 has been compared with insulin glargine in clinical trials of patients with type 2 diabetes who were given basal-bolus insulin or basal insulin plus OHAs.36–38 Basal insulin doses were titrated to target a similar fasting plasma glucose (4·4–5·6 mmol/L). After 6 months of treatment, HbA1c reduction was equivalent between regimens, although use of glargine U300 was associated with fewer instances of nocturnal confirmed hypoglycaemia (≤70 mg/dL) or severe hypoglycaemia.36–38 Thus far, the ultra-long pharmacokinetic profile of the novel, long-acting insulin analogues provides the clinical benefit of reduced cases of nocturnal hypoglycaemia. Whether the use of these and other insulins in development with increasingly long and flat profiles will lead to improved glycaemic control has yet to be shown. Moreover, possible benefits of the novel analogues will still need to be balanced by long-term safety and efficacy data.
Rapid-acting analogues Although basal insulin is preferred for initiation of insulin treatment in patients with type 2 diabetes, many individuals then later advance to a disease stage when prandial insulin is necessary. Rapid-acting insulin analogues were introduced to the market in the mid1990s and have undergone continuous developments (table 2). These analogues have a faster onset and shorter duration of action than human insulin and provide more control of post prandial glucose than does human insulin, with no significant difference in the risk of hypoglycaemia.39 However, the pharmacokinetic profile of rapid-acting insulins is far from ideal because they only estimate the pattern of physiological insulin release. In particular, these insulin analogues cannot fully reproduce the prompt increase in circulating insulin upon ingestion of a meal. In the past decade, several attempts have been made to develop ultra-rapid-acting insulins, many of which have focused on conjugation with excipients or enzymes that accelerate absorption of 4
insulin monomers, whereas other approaches have attempted to change insulin pharmacokinetics by affecting route of delivery (table 2). Changes in the formulation of subcutaneously injected insulin to increase insulin absorption rate has been attempted by different manipulations. Addition of edetic acid, a chelator of zinc, to the insulin hexamer (BioD-090, VIAject; Biodel Inc, Danbury, CT, USA)40 causes a more rapid dissociation of the hexamer into dimers and monomers when subcutaneously injected, resulting in a faster maximum glucose-lowering effect. Overall experience of rapid-acting analogues in patients with type 2 diabetes is small and very rare. In 14 patients with type 2 diabetes, a single dose of BioD-090, human regular insulin, or insulin lispro before a test of a standardised liquid meal was associated with comparable absolute plasma glucose concentrations and similar timecourse of plasma glucose concentrations between insulin types.41 Injection of a rapid-acting insulin with recombinant human hyaluronidase (rHuPH20)42 leads to disruption of the hyaluronic acid in the subcutaneous adipose layer, enabling a more rapid spread of the locally injected insulin, and better absorption than rapid-acting insulins without rHuPH20. In a trial including 21 patients with type 2 diabetes, use of insulin lispro with rHuPH20 provided better control of glycaemic excursion than with lispro alone, with lower insulin requirements and lower hypoglycaemic excursion, as indicated by an improvement of both hyperglycaemic (area under the curve [AUC]0–4h >7·8 mmol/L, 56% of control, p=0·48) and hypoglycaemic (AUC0–8 h
