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Novel and Emerging Insulin Preparations for Type 2 Diabetes
Can J Diabetes 39 (2015) S160–S166
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Canadian Journal of Diabetes journal homepage: w w w. c a n a d i a n j o u r n a l o f d i a b e t e s . c o m
Innovations in Diabetes Care
Novel and Emerging Insulin Preparations for Type 2 Diabetes Kitty Kit Ting Cheung BSc, MBChB, MRCP(UK), FHKCP, FHKAM(Med) a,b, Peter Alexander Senior BMedSci, MBBS, PhD, FRCP a,* a b
Clinical Islet Transplant Program, Division of Endocrinology, Department of Medicine, University of Alberta, Edmonton, Canada Division of Endocrinology and Diabetes, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong, China
a r t i c l e i n f o Article history: Received 11 July 2015 Received in revised form 18 September 2015 Accepted 23 September 2015
Introduction
Rising Prevalence and Burden of Diabetes in Canada
The prevalence of type 2 diabetes is rising in Canada, and the burden of this disease on our healthcare system is getting heavier each year and is reflected by the alarming morbidity and mortality associated with it. Insulin has been a pivotal player in the management of selected patients with type 2 diabetes; however, currently available insulin preparations have their limitations. To date, a few emerging basal insulins, such as degludec, peglispro and Gla-300, will soon be available for use and show promising results in multiple phase 3 clinical trials in a broad spectrum of individuals with type 2 diabetes. The major benefits of these new insulin preparations are the reduction of risk for hypoglycemia due to their flatter profile and the allowance of flexibility owing to their longer duration of action. Despite these advantages, subcutaneous insulin injections are considered by patients to be invasive and inconvenient. In particular, prandial insulin, which requires frequent injections, is not well accepted by them. Also, local effects of insulin on injection sites, such as lipodystrophy and allergy, hinder the use of subcutaneous insulin in a proportion of patients. Newer strategies involving clever devices and formulations, such as inhaled, buccal, transdermal and oral insulins are in the pipeline. With all these options becoming available in the near future, physicians have to be reminded that the ultimate treatment regime should be based on the efficacy, side-effect profiles, patients’ options and cost-effectiveness of the drugs. The importance of individualized risk stratification and personalized care in order to maximize benefits and minimize harm should always be kept in mind.
According to the Canadian Diabetes Association, 3.3 million people were diagnosed with diabetes in Canada in 2014, and 1 million Canadians were living with undiagnosed type 2 diabetes and 5.7 million people with prediabetes (1). More than 50% of Canadians diagnosed with diabetes were of working age, between 25 and 64 years of age. During the past decade, the prevalence of diagnosed diabetes among Canadians has increased by 70%, with the greatest relative increase in prevalence occurring in the 35- to 44-year age group, driven in part by increasing rates of overweight and obesity. It has been estimated that the number of Canadians living with diabetes will reach 3.7 million by 2018 to 2019 (2). The costs of treating diabetes and its complications has risen tremendously in recent years. Canadians with diabetes are 3 times more likely to be hospitalized with cardiovascular disease (CVD) than those without the disease, 12 times more likely to be admitted with end stage renal disease (ESRD) and 20 times more likely to have nontraumatic lower-limb amputations due to peripheral vascular disease (PVD). When hospitalized, they have longer hospital stays than people without diabetes. The annual per capita healthcare costs have been estimated to be 3 to 4 times greater than those in the population without diabetes; 3.1% of all deaths in Canada were caused by diabetes in 2007, and close to 30% of patients who died had diabetes in 2008 and 2009. Most of the time, complications of diabetes, particularly macrovascular disease, were the leading causes of mortality. In all age groups, people with diabetes had mortality rates at least 2 times higher than those without diabetes (2).
Morbidity and Mortality: The Definition of Good Diabetes Control * Address for correspondence: Peter Alexander Senior, BMedSci, MBBS, PhD, FRCP, Clinical Islet Transplant Program, University of Alberta, #2000 8215 112 Street, Edmonton, Alberta T6G 2C8, Canada. E-mail address: [email protected]
The morbidity and mortality associated with the increasing prevalence of diabetes have led to considerable effort to find strategies that prevent, manage and cure the disease. Data from the pivotal
1499-2671 © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjd.2015.09.082
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UK Prospective Diabetes Study (UKPDS) trial in newly diagnosed and relatively healthy patients with type 2 diabetes have shown that tight glycemic control could reduce the incidence and severity of the microvascular complications of diabetes (3). The impact of glycemic control on macrovascular complications was examined in 3 more recent large, though relatively short, clinical trials in individuals with established diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE) and Veterans Affairs Diabetes Trial (VADT) studies did not demonstrate significant reductions in macrovascular outcomes with intensive glycemic control and led to substantial concern that “the lower the better” might not be as valid a concept, as has been previously believed (4–6). In particular, the ACCORD study was stopped early due to an increased risk for mortality in patients who underwent intensive blood glucose lowering (4). Potential long-term benefits of glycemic control for macrovascular disease, even in patients with established type 2 diabetes, have been identified in the recently published extension phase of VADT, which reported that after approximately 10 years of follow up, individuals with established type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, although there was no difference in mortality (7). Given the phenotypic heterogeneity and multicausality of morbidity and mortality in people with type 2 diabetes, most professional guidelines now call for individualized risk stratification and personalized care in order to maximize benefits and minimize harm (8).
The Role of Insulin in Type 2 Diabetes and the Limitations Despite the availability of multiple new oral agents and noninsulin therapies, progressive decline in beta cell function and, consequently, glycemic control continue to be the norm in patients with established type 2 diabetes, and many people will eventually need insulin as treatment. Exogenous insulin preparations administered subcutaneously are used in patients with type 2 diabetes with the aim of mimicking healthy pancreatic function through long-acting injections (basal insulin) and short-acting injections with meals (bolus/prandial insulin) (Table 1). However, limitations exist in all of the currently available forms of insulin on the market. Hypoglycemia and weight gain are the most recognized and feared side effects of subcutaneous insulin. In 2007, the UK Hypoglycemia Study Group reported the incidence of severe hypoglycemia of 320 episodes per 100 patient-years in patients with type 1 diabetes who had been treated with insulin for >15 years (9). The incidence was 70 episodes per 100 patient-years for patients with type 2 diabetes who had been treated with insulin for >5 years (9). In the UKPDS, patients with type 2 diabetes gained an average of 7 kg after 10 years of insulin treatment, with the most rapid weight gain occurring when insulin was first initiated (3). The need for frequent injections,
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sometimes with very large doses or volumes of insulin, required by insulin-resistant patients can be barriers to optimal compliance and may limit the effectiveness of current insulin-based therapies. Limitations of currently available basal insulin preparations Currently, basal insulin treatments can be provided by neutral protamine Hagedorn (NPH) human insulin or long-acting insulin analogues. NPH insulin has a duration of action of 8 to 12 hours, requiring twice-daily injections to cover a 24-hour period. Compared to the long-acting insulin analogues, NPH insulin has higher risk for causing nocturnal and severe hypoglycemia due to its peak effects, which occur 4 to 6 hours after injection. Because NPH is supplied as a suspension, if inadequately suspended prior to use, it will lead to inconsistent glycemic control, which manifests as substantial glycemic variability between and within days. The long-acting basal insulin analogues, glargine and detemir, provide a flatter and more physiologic basal insulin, leading to safer glycemic profiles with lower risks for nocturnal or severe hypoglycemia in patients with type 2 diabetes. Although no clinically relevant differences in efficacy or safety between glargine and detemir have been established, an analysis involving a total of 7 large randomized controlled trials comparing glargine and detemir in patients with type 1 diabetes or type 2 diabetes arrived at the conclusion that higher doses of detemir as compared with glargine may be needed to achieve the same glycemic control. Also, twice-daily injections of detemir should be considered in those whose glucose control starts to decline after 12 hours (10). Substantial variability in the duration of action of any specific insulin between or within individuals has been observed, confounding management of diabetes (11). One reason for the variability is the variation in insulin administration technique, such as incomplete suspension of NPH or premixed insulin, variable injection depths and differing speeds of needle withdrawal. Differences in the properties of insulin, including solubility, dose, concentration, albumin-binding and self-association rate, are other reasons. Finally, physiologic factors, such as blood flow, skin temperature, adiposity, injection site and changes in insulin sensitivity due to changes in insulin antagonistic hormones, such as glucagon, growth hormone, cortisol and catecholamines, are also important determinants of inter- and intraindividual glucose variability. Until this moment, only 1 basal insulin with duration of action of up to or longer than 24 hours, Gla-300 (Glargine U300, Toujeo, sanofi-aventis Canada, Laval, Quebec), has recently become available in the Canadian market. Many patients are still taking frequent subcutaneous injections, which are considered inconvenient and invasive. Gla-300 Gla-300 is an insulin designed to optimize glycemic control while minimizing the risk for hypoglycemia. It is basically a more concentrated form of glargine than that currently available on the market
Table 1 Currently available insulin formulations on the Canadian market Insulin type
Generic name
Brand name
Duration of action (hours)
Fast acting (bolus/prandial) insulin
• • • • • •
Lispro Aspart Glulisine Regular Regular Neutral protamine Hagedorn (NPH)
3 to 5
• • •
Glargine Determir Glargine U300
• • • • • • • • • •
Human insulin
Basal insulin
Humalog NovoLog Apidra Humulin R Novolin Toronto Humulin N Novolin NPH Lantus Levemir Toujeo
5 to 8 12 to 16 Up to 24
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(300 unit/mL vs. 100 unit/mL). Because of its higher concentration, after subcutaneous injection of a smaller volume as compared to the regular glargine U100, the action profiles of Gla-300 were more flat and prolonged, rendering a more gradual and extended release of glargine from the subcutaneous depot (12). A meta-analysis of 3 phase-3 noninferiority studies, the Efficacy and safety of Gla-300 compared with Gla-100 in DIfferent patient populaTIONs (EDITION) 1, 2 and 3 trials, comparing the efficacy and safety of Gla-300 with glargine U100 in patients with type 2 diabetes on basal and mealtime insulin, basal insulin plus oral antihyperglycemic agents or no prior insulin, respectively, reported that Gla-300 provided glycemic control comparable to that of glargine U100 in a large population having a broad spectrum of type 2 diabetes, with less hypoglycemia at any time of the day and consistently less nocturnal hypoglycemia (13). Emerging basal insulin preparations In view of the above, pharmaceutical companies are now racing to come up with insulin formulations with flatter profiles and with durations of action beyond 24 hours. Most of them are using complex insulin analogues in this pursuit (Table 2). All of the new basal insulin preparations shown in Table 2, have been tested in phase-3 clinical trials data in patients with type 2 diabetes (14). Degludec Degludec is a long-acting basal insulin that forms multihexamers when injected into subcutaneous tissue, with a half-life (25 hours) twice as long as that of currently available basal insulins and a prolonged (42 hours) duration of effect (15). The pharmacologic nature of this drug allows for flat and persistent basal insulin levels that provide steady coverage for more than 24 hours (16). The primary advantages are reduction in nocturnal hypoglycemia and
flexibility of dosing regimen if patients miss or delay doses, in comparison to glargine (17). It has been licensed in Europe by the European Medicines Agency (EMA) in 2 forms since January 2013 (degludec and degludec/aspart combination) (18). These 2 medications have also been approved in Mexico and Japan. Several phase-3 studies with noninferiority design have been commenced since 2009 to assess the efficacy of once-daily degludec, either alone or as an add-on therapy, as compared to once-daily glargine, including a 26-week pan-Asian trial (BEGIN-Asia), a 26-week low-volume 200 unit/mL formulation of degludec (BEGIN Low Volume) and 2 52-week studies (the BEGIN Once Long study in insulin-naive patients and the BEGIN Basal-Bolus Type 2 study in insulin-experienced users). All reports showed that degludec was associated with lower risks for hypoglycemia in patients with type 2 diabetes than was glargine, while offering similar longterm glycemic control (Table 3) (19–22). Further, an important advantage of degludec, the allowance for flexibility in injection time, was proven in the BEGIN Flex trial, in which, after 26-weeks of flexible dosing with degludec (given in a schedule with a minimum of 8 and a maximum of 40 hours between doses), the glycemic control was not statistically different from that of glargine in terms of the glycated hemoglobin (A1C) levels (−1.28% vs. −1.26%) and the proportion of patients achieving A1C levels of <7% (38.9% vs. 43.9%) (23). However, the cardiovascular safety of degludec has been questioned. A global phase-3 double-blind, randomized trial comparing the cardiovascular safety of degludec vs. glargine in subjects with type 2 diabetes at high risk for cardiovascular events (DEVOTE) is ongoing, and preliminary data are expected to be available by the end of 2016, upon completion of the trial (24). Peglispro Peglispro is a new basal insulin analogue that is being studied as a once-daily treatment. In comparison to glargine, it has been
Table 2 Emerging basal insulin Pharmaceutical company
Insulin
Dosing
Phase of clinical trials
Formulation
Ascendis
Transcon hydrogel insulin (ACP-002) (52)
Potentially weekly
Insulin analogue
Novo Nordisk Hanmi Pharmaceutical PhaseBio Eli Lilly
LAI287 (NN1436) (53) LAPS-Insulin 115 (HM12470) (54) PE0319 (55) PEGlispro (BIL) (25)
Weekly Weekly Weekly Daily
Novo Nordisk
Tresiba (degludec) (NN1250) (56)
Every 1 to 2 days
Preclinical: Sanofi recently backed out from a 2010-codevelopment deal Phase 1 Phase 1 Phase 2: No clinical data published yet Phase 3: FDA and EMA submissions delayed (see text) FDA accepted resubmission, already available on market in Europe, Mexico and Japan
Insulin analogue Insulin analogue Insulin analogue Insulin analogue Insulin analogue
Table 3 Summary of A1C and hypoglycemia data on emerging basal insulin from phase 3 clinical trials with noninferiority design in type 2 diabetes Basal insulin
Clinical trials
Comparator
Patients
A1C (%)
Nocturnal hypoglycemia
Severe Hypoglycemia
Total Hypoglycemia
Degludec (51)
BEGIN
Glargine
IMAGINE
Glargine
ETD Degludecglargine 0.05, p=0.44 Glargine vs. peglispro 7.2±0.04 vs. 6.9±0.03, p<0.001
21% lower in degludec, RR 0.79, p=0.02 Glargine vs. peglispro 15.7±0.7 vs. 14.5±0.6, RR 0.92, p>0.05
T2D on basal-bolus insulin
7.0±0.0 vs. 6.8±0.0, p<0.001 ETD Degludec-Glargine 0.00 (95% CI −0.08– 0.07)
52% lower in degludec, RR 0.48, p<0.01 Glargine vs. peglispro 5.8±0.5 vs. 3.8±0.2, RR 0.64, p<0.001 11±0.6 vs. 6.2±0.4, RR 0.55, p<0.001 31% lower in Gla300, p=0.0002
—
Peglispro (21)
T2D who required >60 units of insulin doses at the end of the trials T2D on basal insulin only
Gla-300 (26)
EDITION
Glargine
T2D on basal-bolus insulin, T2D on basal insulin and oral antihyperglycemic agents, T2D insulin naïve
Glargine vs. peglispro 0.80 vs. 0.34, RR 0.43, p>0.05 4.72 vs. 5.24, RR 1.12, p>0.05 14% lower in Gla300, p=0.0116
Note: A1C, glycated hemoglobin; CI, confidence interval; ETD, end of treatment difference; RR, relative risk; T2D, type 2 diabetes.
66±2.3 vs. 73±2.4, RR 1.10, p>0.05 —
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shown to be associated with a small amount of weight loss (25). The effect of weight loss may be due to the avoidance of overinsulinization of peripheral tissues as compared to glargine because peglispro has a larger hydrodynamic size and a prolonged duration of action, leading to a delay in insulin absorption, and is, therefore, preferentially taken up in liver via the portal circulation than by muscles or adipose tissues. Peglispro appears to have a preferential hepatic action compared with peripheral tissues relative to glargine (which is similar to human insulin) because glucose disposal rates are lower with peglispro than with glargine when given at doses suppressing hepatic glucose production (25). This seems to result in a more physiologic hepatic-to-peripheral insulin gradient, leading to effective suppression of endogenous glucose production by the liver while minimizing antilipolytic actions in peripheral tissues. In a phase 2 study performed in more than 300 subjects with type 2 diabetes and mean diabetes duration of 12 years who were already taking oral antihyperglycemic agents and insulin, peglispro and glargine had comparable glucose control (fasting glucose 6.6±0.1 mmol/L vs. 6.5±0.2 mmol/L; p=0.433; A1C 7.0±0.1 vs. 7.2±0.1%; p=0.279), but peglispro showed reduced intraday glycemic variability (1.9 mmol/L vs. 2.2 mmol/L; p=0.031); lower nocturnal hypoglycemia rates (as defined by blood glucose levels of ≤3.9 mmol/L or signs or symptoms associated with hypoglycemia); 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (p=0.021); and, although there was no statistically significant difference between groups, peglispro appeared to be associated with a small amount of weight loss relative to glargine (change from baseline −0.6±0.2 kg, p=0.007 vs. 0.3±0.2 kg, p=0.662). No patient in either treatment group experienced severe hypoglycemia (as defined by signs or symptoms requiring assistance from another person because of severe neurologic impairment and, in the absence of blood glucose measurement, responded promptly to carbohydrate intake or administration of glucagon or intravenous glucose) (26). Phase 3 noninferiority and superiority studies comparing oncedaily peglispro and once-daily glargine in patients with type 2 diabetes have been completed, and early information on the outcomes of these studies revealed good efficacy in glucose control and reduced risk for hypoglycemia (Table 3). IMAGINE-2, a 52-week trial in insulin-naive patients; IMAGINE-4, a 26-week trial using peglispro or glargine in combination with prandial insulin; and IMAGINE-5, a 52-week trial evaluating peglispro compared to glargine in patients who were already on a basal insulin, are the most recently published studies. Compared with glargine, peglispro use in patients with type 2 diabetes led to more patients’ achieving A1C levels of <7% and less reported nocturnal hypoglycemia, although the rates of total hypoglycemia did not differ significantly between the 2 treatment groups (Table 3). Weight gain was less in patients taking peglispro, as reported in the IMAGINE-2 and IMAGINE-4 studies (27). Despite these promising results, the originally planned submissions of regulatory filings of peglispro with the US Food and Drug Administration (FDA) and EMA in the first quarter of 2015 were delayed until after 2016, according to the company announcement in February 2015, claiming that further evaluation of the safety and efficacy of this investigational treatment are needed (25). In particular, individuals with type 2 diabetes and taking peglispro who were already on insulin before were noted to have increased liver fat content (from 10% at baseline to 15% at 52 weeks of treatment) as compared to glargine (unchanged), although no acute or severe hepatocellular drug-induced liver injuries were apparent after 78 weeks of peglispro treatment (28). Another major safety concern was a rise of up to 25% in triglyceride levels in patients with type 2 diabetes; they were observed only in subjects previously treated with insulin but not in those who were insulin naive.
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Increased adipose tissue release of free fatty acids, decreased adipose tissue lipoprotein lipase activity or increased de novo hepatic lipogenesis, either alone or in combination, were the mechanisms proposed (29). None of these insulin preparations (degludec, peglispro and Gla300) have yet been demonstrated to be safe in pregnancy and, therefore, are not recommended during pregnancy. Will Biosimilar Insulin Analogues Resolve Financial Barriers to Access? Although insulin analogues that are currently available on the market are associated with fewer episodes of hypoglycemia than conventional insulins, they are costly, and their use has to be justified. Several cost-effectiveness analyses have confirmed that the use of insulin analogues in patients with type 1 diabetes is favourable (30,31). Both glargine and detemir were either less costly and more effective or more costly but more effective than NPH in subjects with type 1 diabetes (31). In 2014, the EMA authorized the first biosimilar of glargine, LY2963016 insulin glargine (LY IGlar) 100 units/mL, for treatment of diabetes (32), signifying a possible solution to combat the high cost of insulin analogues. LY IGlar is a long-acting human insulin analogue that has an identical amino acid sequence and the same pharmaceutical strength as glargine (33). In the recent ELEMENT 1 study, LY IGlar showed efficacy similar to that of glargine in patients with type 1 diabetes when repeated once-daily dosing over 24 and up to 52 weeks (33). In the ELEMENT 2 study, the effectiveness of this biosimilar insulin, in addition to the use of oral antihyperglycemic agents, in patients with type 2 diabetes was also proven (34). More biosimilar insulins are likely to be entering the market of diabetes therapies when patents for major branded insulin analogues start to expire in the coming years. Endogenous vs. exogenous insulin delivery In individuals without diabetes, insulin is secreted from pancreatic beta cells and enters the circulation via the portal vein, where the liver extracts about 70% due to the first-pass effect. Therefore, systemic circulating insulin concentrations are reduced compared with those in the portal system, and subsequent insulin effects in the peripheral tissues are also reduced compared with the liver (35). The liver is vital in maintaining the fasting plasma glucose levels. The basal rate of tissue glucose uptake is precisely balanced by the rate of endogenous glucose production during the fasting state. In contrast, after ingestion of food, this balance is disrupted, and the homeostasis in the fed state is regulated by the suppression of endogenous gluconeogenesis, enhanced glucose uptake by peripheral tissues and stimulation of glucose oxidation (36). Until recent times, exogenous insulin administration for diabetes has been available only through the subcutaneous route by which insulin is introduced into the body in a nonphysiologic way. The invasive and inconvenient nature of insulin injections may not be well accepted by patients. As a result, many patients decline or delay insulin therapy, leading to suboptimal diabetes control. Even when patients accept insulin injections, the risk for hypoglycemia and lipodystrophy limits the safety and efficacy profiles of insulin injections. The nonphysiologic low hepatic-to-peripheral insulin gradient is another big disadvantage. When insulin is injected subcutaneously, the insulin concentrations in the peripheral tissues are much higher than those in the liver. With this overinsulinization of peripheral tissues, muscle and adipose tissues take up a lot of glucose. The antilipolytic effect of insulin in the peripheral tissues leads to weight gain. In the liver, because the insulin level is low, it is hard to suppress endogenous glucose production, causing suboptimal diabetes control (37).
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Limitations of current bolus insulin preparations Currently available rapid-acting insulin preparations (Table 1) are considered to be too slow in onset of action (10 to 20 minutes) and too long lasting (3 to 5 hours), leading to problematic hypoor hyperglycemia. Co-injection of hyaluronidase, which is known for its abilities to increase the dispersion and absorption of subcutaneously administered drugs due to its physical properties, has been shown to accelerate subcutaneous insulin absorption. In a small study carried out in 21 individuals with type 2 diabetes, co-injection of lispro and recombinant human hyaluronidase accelerated the pharmacokinetics of lispro (time to peak insulin concentration, 43 vs. 74 minutes; p=0.0045) with increased exposure in the first hour (184% of control; p<0.0001) and reduced exposure after 2 hours (67% of control; p=0.0001). This translated into superior control of postmeal glycemic surge with lower insulin requirements and also reduced hypoglycemic events (38). Newer routes for insulin delivery To address some of the limitations associated with subcutaneous delivery of insulin, alternative routes of insulin delivery have been proposed; some of them show promising effects for glycemic control. Nasal and respiratory delivery The lungs provide a huge surface area, making them an ideal site for insulin delivery as an alternative to the subcutaneous route. Furthermore, delivering insulin nasally would avoid gastrointestinal degradation. The first inhaled insulin was Exubera, which was approved by the FDA in 2006 for use in patients with both type 1 and type 2 diabetes. It had been proven to be well-tolerated in long-term use in poorly controlled patients with type 2 diabetes (39). However, it was later withdrawn from the market by the manufacturer because it was deemed to not be cost-effective. The latest and the only inhaled insulin, which has recently become available on the market, is Afrezza, a rapid-acting inhalation prandial insulin in powder form. It is delivered through a tiny plastic inhaler, and all the patients need to do is to put the insulin cartridge into it and inhale before each meal (40). The FDA approved, it, in 2014, for use in patients with type 1 and type 2 diabetes who do not smoke and do not have lung disease in (41). Prior to starting, it is advised that patients should have pulmonary function tests as baseline assessments to make sure the patients are fit for this medication (42). Afrezza has been tested in 2 phase-3 clinical trials involving patients with type 2 diabetes. The results from these trials have not yet been published, but early results are promising. For patients who were insulin naive, 24 weeks of Afrezza use led to a statistically significant greater mean reduction in A1C levels than that in those taking a placebo inhaler (−0.82% vs. −0.42%), and the percentage of patients reaching A1C levels ≤7% was 32.2% as compared to 15.3% with placebo. For patients who were already taking insulin, Afrezza plus bedtime glargine was noninferior to twice-daily premixed subcutaneous insulin with 70% NPH and 30% aspart (40,43). However, because Afrezza is a rapid-acting insulin, it does carry risks for hypoglycemia. No statistically significant differences in the occurrence of hypoglycemic events were noted in a clinical trial that compared Afrezza with oral antihyperglycemic agents (0.7±1.6 event/ month vs. 0.9±1.9 event/month respectively; p=0.321) (44), whereas patients taking Afrezza with glargine had statistically fewer hypoglycemic episodes than those taking premixed subcutaneous insulin (mild to moderate hypoglycemia 48% vs. 69%, respectively; p<0.0001; severe hypoglycemia 4.33% vs. 9.97%, respectively; p<0.007) (40). Whether the lower rate of hypoglycemia was due to the superiority of Afrezza or that of glargine cannot be determined.
Compared with subcutaneous insulin, much larger doses of inhaled insulin are needed for glycemic control. Because the doses differ from conventional units, conversion can cause confusion and error when patients are being switched from the subcutaneous to the inhaled form. Flexibility is another limitation because inhaled insulin comes in cartridges containing fixed amounts. For Afrezza, only 4-unit and 8-unit cartridges are available, making fine titration and precise dosing impossible. Inhaled insulin does cause more dry cough and has been shown to cause reversible reduction of pulmonary function. Last but not least, there is still uncertainty related to the long-term safety of this new product. In a clinical trial, 2 subjects with histories of heavy smoking developed lung cancer while using Afrezza, compared to no subjects using the comparator. After completion of the trial, 2 more cases of lung cancer were reported in nonsmokers who had taken Afrezza (43). Currently, a 5-year clinical trial of Afrezza to assess long-term cancer risk is under way, as required by the FDA. With the above said, inhaled insulin remains a logical option for patients with needle phobia, injection-site problems or unwillingness to take subcutaneous insulin. Buccal The buccal mucosa has an abundant blood supply and, therefore, is another alternative route being considered for noninvasive insulin delivery. Similar to nasal insulin, buccal delivery of insulin avoids gastrointestinal degradation. In 2009, the FDA approved OralLyn, an insulin spray, conditionally under its Investigational New Drug (IND) program, for patients with type 1 and type 2 diabetes who are suffering from serious or life-threatening diabetes, who have no satisfactory alternative treatments and who are not eligible for participation in the phase 3 clinical trial of the drug. The spray delivers prandial insulin through a device that sprays insulin on the cheek; however, only 10% of the insulin delivered is absorbed (45). A new buccal system is currently under development; it aims to deliver insulin using a small film with fixed thickness and shape and might be particularly useful in psychiatric and geriatric patients due to its ease of use, its tastelessness and its quick-dissolution properties (46). Transdermal The skin is the largest organ of the body that allows absorption of insulin into the blood stream with avoidance of gastrointestinal degradation. The dermis has a rich blood supply, in contrast to the relatively poorly vascularized subcutaneous tissue currently used. Transdermal insulin is painless and allows for easy handling by patients. Although intact skin is an effective barrier for the body with low permeability that prevents the passage of insulin, several technologies have been employed to overcome this barrier, and some of them are now already in clinical trials or on the market. Microneedles combined with drug patches are a system involving tiny needles with a mean diameter of 1 μm (micron) and a length range of 1 to 100 μm. Microneedles pierce the skin openings into microchannels to allow the transport of insulin through the skin. Because they penetrate only down to the stratum corneum due to their microsize, nerve endings are not reached and, therefore, no pain is elicited (47). Currently, a device employing this technology called V-Go, which delivers a continuous preset basal rate of insulin (20, 30 or 40 units of insulin in a 24-hour period) and allows on-demand bolus dosing at mealtimes has already been approved by the FDA for use in patients with type 2 diabetes. This device is compatible with both aspart and lispro (48). Phospholipid insulin-containing vesicles, which are elastic, flexible and deformable and allow for squeezing into the pores of skin, are another technology currently being examined (49). Last, iontophoresis, a technique that employs small electric currents for enhancing the skin’s permeability to accept insulin, is currently being
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tested in animal studies. In rats, iontophoresis drove the insulinloaded nanovesicles into the deep layers of the skin, which allowed the release and gradual absorption of insulin (50). Oral Insulin administered orally has the potential to be taken up by the gastrointestinal tract, delivered to the portal vein and transported directly to the liver, mimicking the pathway of endogenous insulin and producing a physiologic hepatic-to-peripheral insulin gradient. However, insulin is not lipophilic and has a large molecular weight, making it hard to be absorbed. As well, enzymatic degradation in the stomach, inactivation by gastric acid, digestion by enzymes in the intestinal lumen and poor permeability across the intestinal epithelium all contribute to the low oral bioavailability of oral insulin preparations. Newly devised strategies, such as enteric coated tablets, absorption enhancers, enzyme inhibitors, insulin chemical modifications and special carriers are now being studied with the hope of increasing the oral bioavailability of insulin (51).
Conclusions In summary, a large number of novel insulin molecules, preparations and delivery systems are being developed as tools to improve the management of type 2 diabetes, with the ultimate goal of reducing the burden of diabetes for individuals, improving health and reducing morbidity and mortality. Some of these approaches, particularly the new basal insulins, such as Gla-300, degludec and peglispro, seem to have particular benefits for patients experiencing, or at risk for, frequent hypoglycemia based on consistent reductions of hypoglycemia, as demonstrated in phase 3 clinical trials. The availability of more concentrated insulin preparations (U-200, U-300) may have benefits because of improved pharmacokinetics, but they also may be particularly useful in improving patient comfort and acceptance, particularly in individuals with very high insulin requirements. The potentials for new routes of insulin delivery are intriguing, but it remains to be seen whether the stated preference to avoid injections will translate into a preference of prescribers and users to use these alternative agents, given the relatively low uptake of inhaled insulin thus far. A further common but major hurdle will be the willingness of payers to reimburse novel therapies. Novel insulin products are generally required to demonstrate equivalent (noninferiority) glycemic control potential, and because most pharmacoeconomic models are based heavily on reduction of A1C levels for prevention of complications and may not include or adequately estimate the costs of hypoglycemia, it may be difficult to demonstrate cost-effectiveness. Patient-reported outcomes and quality-of-life studies may become more important as tools to assess the advantages of newer products. The capacity of physicians to individualize care with insulin is now greater than ever because of these emerging insulins and delivery strategies. The increasing numbers of options for insulin therapy, together with the growth in oral and injectable antihyperglycemic agents, are challenging for physicians and healthcare professionals working to care for patients with diabetes. No matter how many options there are, efficacy, side-effect profile, patient preference and cost-effectiveness should remain the cornerstones when deciding on treatment regimens.
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Mathieu C, Hollander P, Miranda-Palma B, et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): A 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab 2013;98:1154–62. 24. . 25. . 26. Bergenstal RM, Rosenstock J, Arakaki RF, et al. A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care 2012;35:2140–7. 27. . 28. Buse J, Rodbard H, Serrano C, et al. Superior HbA1c Reduction with Basal Insulin Peglispro (BIL) vs Insulin Glargine (GL) Alone or with Oral Antihyperglycemic Medications (OAMs) in T2D Patients (Pts) Previously Treated with Basal Insulin: IMAGINE 5. Abstract 984-P. Presented at 75th American Diabetes Association (ADA) Scientific Sessions; 2015; Boston, MA. 29. Blevins T, Pieber T, Vega G, et al. 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32.. 33. Blevins TC, Dahl D, Rosenstock J, et al. Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus (R)) in patients with type 1 diabetes in a randomized controlled trial: The ELEMENT 1 study. Diabetes Obes Metab 2015;17:726–33. 34. Rosenstock J, Hollander P, Bhargava A, et al. Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus(R)) in patients with type 2 diabetes who were insulin-naive or previously treated with insulin glargine: A randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab 2015;17:734–41. 35. Henry RR, Mudaliar S, Ciaraldi TP, et al. Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects. Diabetes Care 2014;37:2609–15. 36. Singhal P, Caumo A, Carey PE, et al. Regulation of endogenous glucose production after a mixed meal in type 2 diabetes. Am J Physiol Endocrinol Metab 2002;283:E275–83. 37. Turner RC, Holman RR, Stratton IM, et al. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65. 38. Hompesch M, Muchmore DB, Morrow L, et al. Improved postprandial glycemic control in patients with type 2 diabetes from subcutaneous injection of insulin lispro with hyaluronidase. Diabetes Technol Ther 2012;14:218– 24. 39. Barnett AH, Lange P, Dreyer M, et al. Long-term tolerability of inhaled human insulin (Exubera (R)) in patients with poorly controlled type 2 diabetes. Int J Clin Pract 2007;61:1614–25. 40. Rosenstock J, Lorber DL, Gnudi L, et al. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: A multicentre randomised trial. Lancet 2010;375:2244–53. 41. .
42. Santos Cavaiola T, Edelman S. Inhaled insulin: A breath of fresh air? A review of inhaled insulin. Clin Ther 2014;36:1275–89. 43. Abramowicz M, Zuccotti G, Pflomm JM. An inhaled insulin (Afrezza). JAMA 2015;313:2176–7. 44. Rosenstock J, Bergenstal R, DeFronzo RA, et al. Efficacy and safety of technosphere inhaled insulin compared with technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents. Diabetes Care 2008;31:2177–82. 45. Modi P, Mihic M, Lewin A. The evolving rote of oral insulin in the treatment of diabetes using a novel RapidMist™ System. Diabetes Metab Res Rev 2002;18:S38– 42. 46.. 47. Al-Qallaf B, Das DB. Optimizing microneedle arrays to increase skin permeability for transdermal drug delivery. Ann N Y Acad Sci 2009;1161:83–94. 48. ; [accessed 10.07.15]. 53. ; [accessed 10.07.15]. 54. ; [accessed 10.07.15]. 55. ; [accessed 10.07.15].
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Innovations in Diabetes Care
Novel and Emerging Insulin Preparations for Type 2 Diabetes Kitty Kit Ting Cheung BSc, MBChB, MRCP(UK), FHKCP, FHKAM(Med) a,b, Peter Alexander Senior BMedSci, MBBS, PhD, FRCP a,* a b
Clinical Islet Transplant Program, Division of Endocrinology, Department of Medicine, University of Alberta, Edmonton, Canada Division of Endocrinology and Diabetes, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong, China
a r t i c l e i n f o Article history: Received 11 July 2015 Received in revised form 18 September 2015 Accepted 23 September 2015
Introduction
Rising Prevalence and Burden of Diabetes in Canada
The prevalence of type 2 diabetes is rising in Canada, and the burden of this disease on our healthcare system is getting heavier each year and is reflected by the alarming morbidity and mortality associated with it. Insulin has been a pivotal player in the management of selected patients with type 2 diabetes; however, currently available insulin preparations have their limitations. To date, a few emerging basal insulins, such as degludec, peglispro and Gla-300, will soon be available for use and show promising results in multiple phase 3 clinical trials in a broad spectrum of individuals with type 2 diabetes. The major benefits of these new insulin preparations are the reduction of risk for hypoglycemia due to their flatter profile and the allowance of flexibility owing to their longer duration of action. Despite these advantages, subcutaneous insulin injections are considered by patients to be invasive and inconvenient. In particular, prandial insulin, which requires frequent injections, is not well accepted by them. Also, local effects of insulin on injection sites, such as lipodystrophy and allergy, hinder the use of subcutaneous insulin in a proportion of patients. Newer strategies involving clever devices and formulations, such as inhaled, buccal, transdermal and oral insulins are in the pipeline. With all these options becoming available in the near future, physicians have to be reminded that the ultimate treatment regime should be based on the efficacy, side-effect profiles, patients’ options and cost-effectiveness of the drugs. The importance of individualized risk stratification and personalized care in order to maximize benefits and minimize harm should always be kept in mind.
According to the Canadian Diabetes Association, 3.3 million people were diagnosed with diabetes in Canada in 2014, and 1 million Canadians were living with undiagnosed type 2 diabetes and 5.7 million people with prediabetes (1). More than 50% of Canadians diagnosed with diabetes were of working age, between 25 and 64 years of age. During the past decade, the prevalence of diagnosed diabetes among Canadians has increased by 70%, with the greatest relative increase in prevalence occurring in the 35- to 44-year age group, driven in part by increasing rates of overweight and obesity. It has been estimated that the number of Canadians living with diabetes will reach 3.7 million by 2018 to 2019 (2). The costs of treating diabetes and its complications has risen tremendously in recent years. Canadians with diabetes are 3 times more likely to be hospitalized with cardiovascular disease (CVD) than those without the disease, 12 times more likely to be admitted with end stage renal disease (ESRD) and 20 times more likely to have nontraumatic lower-limb amputations due to peripheral vascular disease (PVD). When hospitalized, they have longer hospital stays than people without diabetes. The annual per capita healthcare costs have been estimated to be 3 to 4 times greater than those in the population without diabetes; 3.1% of all deaths in Canada were caused by diabetes in 2007, and close to 30% of patients who died had diabetes in 2008 and 2009. Most of the time, complications of diabetes, particularly macrovascular disease, were the leading causes of mortality. In all age groups, people with diabetes had mortality rates at least 2 times higher than those without diabetes (2).
Morbidity and Mortality: The Definition of Good Diabetes Control * Address for correspondence: Peter Alexander Senior, BMedSci, MBBS, PhD, FRCP, Clinical Islet Transplant Program, University of Alberta, #2000 8215 112 Street, Edmonton, Alberta T6G 2C8, Canada. E-mail address: [email protected]
The morbidity and mortality associated with the increasing prevalence of diabetes have led to considerable effort to find strategies that prevent, manage and cure the disease. Data from the pivotal
1499-2671 © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjd.2015.09.082
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UK Prospective Diabetes Study (UKPDS) trial in newly diagnosed and relatively healthy patients with type 2 diabetes have shown that tight glycemic control could reduce the incidence and severity of the microvascular complications of diabetes (3). The impact of glycemic control on macrovascular complications was examined in 3 more recent large, though relatively short, clinical trials in individuals with established diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE) and Veterans Affairs Diabetes Trial (VADT) studies did not demonstrate significant reductions in macrovascular outcomes with intensive glycemic control and led to substantial concern that “the lower the better” might not be as valid a concept, as has been previously believed (4–6). In particular, the ACCORD study was stopped early due to an increased risk for mortality in patients who underwent intensive blood glucose lowering (4). Potential long-term benefits of glycemic control for macrovascular disease, even in patients with established type 2 diabetes, have been identified in the recently published extension phase of VADT, which reported that after approximately 10 years of follow up, individuals with established type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, although there was no difference in mortality (7). Given the phenotypic heterogeneity and multicausality of morbidity and mortality in people with type 2 diabetes, most professional guidelines now call for individualized risk stratification and personalized care in order to maximize benefits and minimize harm (8).
The Role of Insulin in Type 2 Diabetes and the Limitations Despite the availability of multiple new oral agents and noninsulin therapies, progressive decline in beta cell function and, consequently, glycemic control continue to be the norm in patients with established type 2 diabetes, and many people will eventually need insulin as treatment. Exogenous insulin preparations administered subcutaneously are used in patients with type 2 diabetes with the aim of mimicking healthy pancreatic function through long-acting injections (basal insulin) and short-acting injections with meals (bolus/prandial insulin) (Table 1). However, limitations exist in all of the currently available forms of insulin on the market. Hypoglycemia and weight gain are the most recognized and feared side effects of subcutaneous insulin. In 2007, the UK Hypoglycemia Study Group reported the incidence of severe hypoglycemia of 320 episodes per 100 patient-years in patients with type 1 diabetes who had been treated with insulin for >15 years (9). The incidence was 70 episodes per 100 patient-years for patients with type 2 diabetes who had been treated with insulin for >5 years (9). In the UKPDS, patients with type 2 diabetes gained an average of 7 kg after 10 years of insulin treatment, with the most rapid weight gain occurring when insulin was first initiated (3). The need for frequent injections,
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sometimes with very large doses or volumes of insulin, required by insulin-resistant patients can be barriers to optimal compliance and may limit the effectiveness of current insulin-based therapies. Limitations of currently available basal insulin preparations Currently, basal insulin treatments can be provided by neutral protamine Hagedorn (NPH) human insulin or long-acting insulin analogues. NPH insulin has a duration of action of 8 to 12 hours, requiring twice-daily injections to cover a 24-hour period. Compared to the long-acting insulin analogues, NPH insulin has higher risk for causing nocturnal and severe hypoglycemia due to its peak effects, which occur 4 to 6 hours after injection. Because NPH is supplied as a suspension, if inadequately suspended prior to use, it will lead to inconsistent glycemic control, which manifests as substantial glycemic variability between and within days. The long-acting basal insulin analogues, glargine and detemir, provide a flatter and more physiologic basal insulin, leading to safer glycemic profiles with lower risks for nocturnal or severe hypoglycemia in patients with type 2 diabetes. Although no clinically relevant differences in efficacy or safety between glargine and detemir have been established, an analysis involving a total of 7 large randomized controlled trials comparing glargine and detemir in patients with type 1 diabetes or type 2 diabetes arrived at the conclusion that higher doses of detemir as compared with glargine may be needed to achieve the same glycemic control. Also, twice-daily injections of detemir should be considered in those whose glucose control starts to decline after 12 hours (10). Substantial variability in the duration of action of any specific insulin between or within individuals has been observed, confounding management of diabetes (11). One reason for the variability is the variation in insulin administration technique, such as incomplete suspension of NPH or premixed insulin, variable injection depths and differing speeds of needle withdrawal. Differences in the properties of insulin, including solubility, dose, concentration, albumin-binding and self-association rate, are other reasons. Finally, physiologic factors, such as blood flow, skin temperature, adiposity, injection site and changes in insulin sensitivity due to changes in insulin antagonistic hormones, such as glucagon, growth hormone, cortisol and catecholamines, are also important determinants of inter- and intraindividual glucose variability. Until this moment, only 1 basal insulin with duration of action of up to or longer than 24 hours, Gla-300 (Glargine U300, Toujeo, sanofi-aventis Canada, Laval, Quebec), has recently become available in the Canadian market. Many patients are still taking frequent subcutaneous injections, which are considered inconvenient and invasive. Gla-300 Gla-300 is an insulin designed to optimize glycemic control while minimizing the risk for hypoglycemia. It is basically a more concentrated form of glargine than that currently available on the market
Table 1 Currently available insulin formulations on the Canadian market Insulin type
Generic name
Brand name
Duration of action (hours)
Fast acting (bolus/prandial) insulin
• • • • • •
Lispro Aspart Glulisine Regular Regular Neutral protamine Hagedorn (NPH)
3 to 5
• • •
Glargine Determir Glargine U300
• • • • • • • • • •
Human insulin
Basal insulin
Humalog NovoLog Apidra Humulin R Novolin Toronto Humulin N Novolin NPH Lantus Levemir Toujeo
5 to 8 12 to 16 Up to 24
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(300 unit/mL vs. 100 unit/mL). Because of its higher concentration, after subcutaneous injection of a smaller volume as compared to the regular glargine U100, the action profiles of Gla-300 were more flat and prolonged, rendering a more gradual and extended release of glargine from the subcutaneous depot (12). A meta-analysis of 3 phase-3 noninferiority studies, the Efficacy and safety of Gla-300 compared with Gla-100 in DIfferent patient populaTIONs (EDITION) 1, 2 and 3 trials, comparing the efficacy and safety of Gla-300 with glargine U100 in patients with type 2 diabetes on basal and mealtime insulin, basal insulin plus oral antihyperglycemic agents or no prior insulin, respectively, reported that Gla-300 provided glycemic control comparable to that of glargine U100 in a large population having a broad spectrum of type 2 diabetes, with less hypoglycemia at any time of the day and consistently less nocturnal hypoglycemia (13). Emerging basal insulin preparations In view of the above, pharmaceutical companies are now racing to come up with insulin formulations with flatter profiles and with durations of action beyond 24 hours. Most of them are using complex insulin analogues in this pursuit (Table 2). All of the new basal insulin preparations shown in Table 2, have been tested in phase-3 clinical trials data in patients with type 2 diabetes (14). Degludec Degludec is a long-acting basal insulin that forms multihexamers when injected into subcutaneous tissue, with a half-life (25 hours) twice as long as that of currently available basal insulins and a prolonged (42 hours) duration of effect (15). The pharmacologic nature of this drug allows for flat and persistent basal insulin levels that provide steady coverage for more than 24 hours (16). The primary advantages are reduction in nocturnal hypoglycemia and
flexibility of dosing regimen if patients miss or delay doses, in comparison to glargine (17). It has been licensed in Europe by the European Medicines Agency (EMA) in 2 forms since January 2013 (degludec and degludec/aspart combination) (18). These 2 medications have also been approved in Mexico and Japan. Several phase-3 studies with noninferiority design have been commenced since 2009 to assess the efficacy of once-daily degludec, either alone or as an add-on therapy, as compared to once-daily glargine, including a 26-week pan-Asian trial (BEGIN-Asia), a 26-week low-volume 200 unit/mL formulation of degludec (BEGIN Low Volume) and 2 52-week studies (the BEGIN Once Long study in insulin-naive patients and the BEGIN Basal-Bolus Type 2 study in insulin-experienced users). All reports showed that degludec was associated with lower risks for hypoglycemia in patients with type 2 diabetes than was glargine, while offering similar longterm glycemic control (Table 3) (19–22). Further, an important advantage of degludec, the allowance for flexibility in injection time, was proven in the BEGIN Flex trial, in which, after 26-weeks of flexible dosing with degludec (given in a schedule with a minimum of 8 and a maximum of 40 hours between doses), the glycemic control was not statistically different from that of glargine in terms of the glycated hemoglobin (A1C) levels (−1.28% vs. −1.26%) and the proportion of patients achieving A1C levels of <7% (38.9% vs. 43.9%) (23). However, the cardiovascular safety of degludec has been questioned. A global phase-3 double-blind, randomized trial comparing the cardiovascular safety of degludec vs. glargine in subjects with type 2 diabetes at high risk for cardiovascular events (DEVOTE) is ongoing, and preliminary data are expected to be available by the end of 2016, upon completion of the trial (24). Peglispro Peglispro is a new basal insulin analogue that is being studied as a once-daily treatment. In comparison to glargine, it has been
Table 2 Emerging basal insulin Pharmaceutical company
Insulin
Dosing
Phase of clinical trials
Formulation
Ascendis
Transcon hydrogel insulin (ACP-002) (52)
Potentially weekly
Insulin analogue
Novo Nordisk Hanmi Pharmaceutical PhaseBio Eli Lilly
LAI287 (NN1436) (53) LAPS-Insulin 115 (HM12470) (54) PE0319 (55) PEGlispro (BIL) (25)
Weekly Weekly Weekly Daily
Novo Nordisk
Tresiba (degludec) (NN1250) (56)
Every 1 to 2 days
Preclinical: Sanofi recently backed out from a 2010-codevelopment deal Phase 1 Phase 1 Phase 2: No clinical data published yet Phase 3: FDA and EMA submissions delayed (see text) FDA accepted resubmission, already available on market in Europe, Mexico and Japan
Insulin analogue Insulin analogue Insulin analogue Insulin analogue Insulin analogue
Table 3 Summary of A1C and hypoglycemia data on emerging basal insulin from phase 3 clinical trials with noninferiority design in type 2 diabetes Basal insulin
Clinical trials
Comparator
Patients
A1C (%)
Nocturnal hypoglycemia
Severe Hypoglycemia
Total Hypoglycemia
Degludec (51)
BEGIN
Glargine
IMAGINE
Glargine
ETD Degludecglargine 0.05, p=0.44 Glargine vs. peglispro 7.2±0.04 vs. 6.9±0.03, p<0.001
21% lower in degludec, RR 0.79, p=0.02 Glargine vs. peglispro 15.7±0.7 vs. 14.5±0.6, RR 0.92, p>0.05
T2D on basal-bolus insulin
7.0±0.0 vs. 6.8±0.0, p<0.001 ETD Degludec-Glargine 0.00 (95% CI −0.08– 0.07)
52% lower in degludec, RR 0.48, p<0.01 Glargine vs. peglispro 5.8±0.5 vs. 3.8±0.2, RR 0.64, p<0.001 11±0.6 vs. 6.2±0.4, RR 0.55, p<0.001 31% lower in Gla300, p=0.0002
—
Peglispro (21)
T2D who required >60 units of insulin doses at the end of the trials T2D on basal insulin only
Gla-300 (26)
EDITION
Glargine
T2D on basal-bolus insulin, T2D on basal insulin and oral antihyperglycemic agents, T2D insulin naïve
Glargine vs. peglispro 0.80 vs. 0.34, RR 0.43, p>0.05 4.72 vs. 5.24, RR 1.12, p>0.05 14% lower in Gla300, p=0.0116
Note: A1C, glycated hemoglobin; CI, confidence interval; ETD, end of treatment difference; RR, relative risk; T2D, type 2 diabetes.
66±2.3 vs. 73±2.4, RR 1.10, p>0.05 —
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shown to be associated with a small amount of weight loss (25). The effect of weight loss may be due to the avoidance of overinsulinization of peripheral tissues as compared to glargine because peglispro has a larger hydrodynamic size and a prolonged duration of action, leading to a delay in insulin absorption, and is, therefore, preferentially taken up in liver via the portal circulation than by muscles or adipose tissues. Peglispro appears to have a preferential hepatic action compared with peripheral tissues relative to glargine (which is similar to human insulin) because glucose disposal rates are lower with peglispro than with glargine when given at doses suppressing hepatic glucose production (25). This seems to result in a more physiologic hepatic-to-peripheral insulin gradient, leading to effective suppression of endogenous glucose production by the liver while minimizing antilipolytic actions in peripheral tissues. In a phase 2 study performed in more than 300 subjects with type 2 diabetes and mean diabetes duration of 12 years who were already taking oral antihyperglycemic agents and insulin, peglispro and glargine had comparable glucose control (fasting glucose 6.6±0.1 mmol/L vs. 6.5±0.2 mmol/L; p=0.433; A1C 7.0±0.1 vs. 7.2±0.1%; p=0.279), but peglispro showed reduced intraday glycemic variability (1.9 mmol/L vs. 2.2 mmol/L; p=0.031); lower nocturnal hypoglycemia rates (as defined by blood glucose levels of ≤3.9 mmol/L or signs or symptoms associated with hypoglycemia); 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (p=0.021); and, although there was no statistically significant difference between groups, peglispro appeared to be associated with a small amount of weight loss relative to glargine (change from baseline −0.6±0.2 kg, p=0.007 vs. 0.3±0.2 kg, p=0.662). No patient in either treatment group experienced severe hypoglycemia (as defined by signs or symptoms requiring assistance from another person because of severe neurologic impairment and, in the absence of blood glucose measurement, responded promptly to carbohydrate intake or administration of glucagon or intravenous glucose) (26). Phase 3 noninferiority and superiority studies comparing oncedaily peglispro and once-daily glargine in patients with type 2 diabetes have been completed, and early information on the outcomes of these studies revealed good efficacy in glucose control and reduced risk for hypoglycemia (Table 3). IMAGINE-2, a 52-week trial in insulin-naive patients; IMAGINE-4, a 26-week trial using peglispro or glargine in combination with prandial insulin; and IMAGINE-5, a 52-week trial evaluating peglispro compared to glargine in patients who were already on a basal insulin, are the most recently published studies. Compared with glargine, peglispro use in patients with type 2 diabetes led to more patients’ achieving A1C levels of <7% and less reported nocturnal hypoglycemia, although the rates of total hypoglycemia did not differ significantly between the 2 treatment groups (Table 3). Weight gain was less in patients taking peglispro, as reported in the IMAGINE-2 and IMAGINE-4 studies (27). Despite these promising results, the originally planned submissions of regulatory filings of peglispro with the US Food and Drug Administration (FDA) and EMA in the first quarter of 2015 were delayed until after 2016, according to the company announcement in February 2015, claiming that further evaluation of the safety and efficacy of this investigational treatment are needed (25). In particular, individuals with type 2 diabetes and taking peglispro who were already on insulin before were noted to have increased liver fat content (from 10% at baseline to 15% at 52 weeks of treatment) as compared to glargine (unchanged), although no acute or severe hepatocellular drug-induced liver injuries were apparent after 78 weeks of peglispro treatment (28). Another major safety concern was a rise of up to 25% in triglyceride levels in patients with type 2 diabetes; they were observed only in subjects previously treated with insulin but not in those who were insulin naive.
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Increased adipose tissue release of free fatty acids, decreased adipose tissue lipoprotein lipase activity or increased de novo hepatic lipogenesis, either alone or in combination, were the mechanisms proposed (29). None of these insulin preparations (degludec, peglispro and Gla300) have yet been demonstrated to be safe in pregnancy and, therefore, are not recommended during pregnancy. Will Biosimilar Insulin Analogues Resolve Financial Barriers to Access? Although insulin analogues that are currently available on the market are associated with fewer episodes of hypoglycemia than conventional insulins, they are costly, and their use has to be justified. Several cost-effectiveness analyses have confirmed that the use of insulin analogues in patients with type 1 diabetes is favourable (30,31). Both glargine and detemir were either less costly and more effective or more costly but more effective than NPH in subjects with type 1 diabetes (31). In 2014, the EMA authorized the first biosimilar of glargine, LY2963016 insulin glargine (LY IGlar) 100 units/mL, for treatment of diabetes (32), signifying a possible solution to combat the high cost of insulin analogues. LY IGlar is a long-acting human insulin analogue that has an identical amino acid sequence and the same pharmaceutical strength as glargine (33). In the recent ELEMENT 1 study, LY IGlar showed efficacy similar to that of glargine in patients with type 1 diabetes when repeated once-daily dosing over 24 and up to 52 weeks (33). In the ELEMENT 2 study, the effectiveness of this biosimilar insulin, in addition to the use of oral antihyperglycemic agents, in patients with type 2 diabetes was also proven (34). More biosimilar insulins are likely to be entering the market of diabetes therapies when patents for major branded insulin analogues start to expire in the coming years. Endogenous vs. exogenous insulin delivery In individuals without diabetes, insulin is secreted from pancreatic beta cells and enters the circulation via the portal vein, where the liver extracts about 70% due to the first-pass effect. Therefore, systemic circulating insulin concentrations are reduced compared with those in the portal system, and subsequent insulin effects in the peripheral tissues are also reduced compared with the liver (35). The liver is vital in maintaining the fasting plasma glucose levels. The basal rate of tissue glucose uptake is precisely balanced by the rate of endogenous glucose production during the fasting state. In contrast, after ingestion of food, this balance is disrupted, and the homeostasis in the fed state is regulated by the suppression of endogenous gluconeogenesis, enhanced glucose uptake by peripheral tissues and stimulation of glucose oxidation (36). Until recent times, exogenous insulin administration for diabetes has been available only through the subcutaneous route by which insulin is introduced into the body in a nonphysiologic way. The invasive and inconvenient nature of insulin injections may not be well accepted by patients. As a result, many patients decline or delay insulin therapy, leading to suboptimal diabetes control. Even when patients accept insulin injections, the risk for hypoglycemia and lipodystrophy limits the safety and efficacy profiles of insulin injections. The nonphysiologic low hepatic-to-peripheral insulin gradient is another big disadvantage. When insulin is injected subcutaneously, the insulin concentrations in the peripheral tissues are much higher than those in the liver. With this overinsulinization of peripheral tissues, muscle and adipose tissues take up a lot of glucose. The antilipolytic effect of insulin in the peripheral tissues leads to weight gain. In the liver, because the insulin level is low, it is hard to suppress endogenous glucose production, causing suboptimal diabetes control (37).
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Limitations of current bolus insulin preparations Currently available rapid-acting insulin preparations (Table 1) are considered to be too slow in onset of action (10 to 20 minutes) and too long lasting (3 to 5 hours), leading to problematic hypoor hyperglycemia. Co-injection of hyaluronidase, which is known for its abilities to increase the dispersion and absorption of subcutaneously administered drugs due to its physical properties, has been shown to accelerate subcutaneous insulin absorption. In a small study carried out in 21 individuals with type 2 diabetes, co-injection of lispro and recombinant human hyaluronidase accelerated the pharmacokinetics of lispro (time to peak insulin concentration, 43 vs. 74 minutes; p=0.0045) with increased exposure in the first hour (184% of control; p<0.0001) and reduced exposure after 2 hours (67% of control; p=0.0001). This translated into superior control of postmeal glycemic surge with lower insulin requirements and also reduced hypoglycemic events (38). Newer routes for insulin delivery To address some of the limitations associated with subcutaneous delivery of insulin, alternative routes of insulin delivery have been proposed; some of them show promising effects for glycemic control. Nasal and respiratory delivery The lungs provide a huge surface area, making them an ideal site for insulin delivery as an alternative to the subcutaneous route. Furthermore, delivering insulin nasally would avoid gastrointestinal degradation. The first inhaled insulin was Exubera, which was approved by the FDA in 2006 for use in patients with both type 1 and type 2 diabetes. It had been proven to be well-tolerated in long-term use in poorly controlled patients with type 2 diabetes (39). However, it was later withdrawn from the market by the manufacturer because it was deemed to not be cost-effective. The latest and the only inhaled insulin, which has recently become available on the market, is Afrezza, a rapid-acting inhalation prandial insulin in powder form. It is delivered through a tiny plastic inhaler, and all the patients need to do is to put the insulin cartridge into it and inhale before each meal (40). The FDA approved, it, in 2014, for use in patients with type 1 and type 2 diabetes who do not smoke and do not have lung disease in (41). Prior to starting, it is advised that patients should have pulmonary function tests as baseline assessments to make sure the patients are fit for this medication (42). Afrezza has been tested in 2 phase-3 clinical trials involving patients with type 2 diabetes. The results from these trials have not yet been published, but early results are promising. For patients who were insulin naive, 24 weeks of Afrezza use led to a statistically significant greater mean reduction in A1C levels than that in those taking a placebo inhaler (−0.82% vs. −0.42%), and the percentage of patients reaching A1C levels ≤7% was 32.2% as compared to 15.3% with placebo. For patients who were already taking insulin, Afrezza plus bedtime glargine was noninferior to twice-daily premixed subcutaneous insulin with 70% NPH and 30% aspart (40,43). However, because Afrezza is a rapid-acting insulin, it does carry risks for hypoglycemia. No statistically significant differences in the occurrence of hypoglycemic events were noted in a clinical trial that compared Afrezza with oral antihyperglycemic agents (0.7±1.6 event/ month vs. 0.9±1.9 event/month respectively; p=0.321) (44), whereas patients taking Afrezza with glargine had statistically fewer hypoglycemic episodes than those taking premixed subcutaneous insulin (mild to moderate hypoglycemia 48% vs. 69%, respectively; p<0.0001; severe hypoglycemia 4.33% vs. 9.97%, respectively; p<0.007) (40). Whether the lower rate of hypoglycemia was due to the superiority of Afrezza or that of glargine cannot be determined.
Compared with subcutaneous insulin, much larger doses of inhaled insulin are needed for glycemic control. Because the doses differ from conventional units, conversion can cause confusion and error when patients are being switched from the subcutaneous to the inhaled form. Flexibility is another limitation because inhaled insulin comes in cartridges containing fixed amounts. For Afrezza, only 4-unit and 8-unit cartridges are available, making fine titration and precise dosing impossible. Inhaled insulin does cause more dry cough and has been shown to cause reversible reduction of pulmonary function. Last but not least, there is still uncertainty related to the long-term safety of this new product. In a clinical trial, 2 subjects with histories of heavy smoking developed lung cancer while using Afrezza, compared to no subjects using the comparator. After completion of the trial, 2 more cases of lung cancer were reported in nonsmokers who had taken Afrezza (43). Currently, a 5-year clinical trial of Afrezza to assess long-term cancer risk is under way, as required by the FDA. With the above said, inhaled insulin remains a logical option for patients with needle phobia, injection-site problems or unwillingness to take subcutaneous insulin. Buccal The buccal mucosa has an abundant blood supply and, therefore, is another alternative route being considered for noninvasive insulin delivery. Similar to nasal insulin, buccal delivery of insulin avoids gastrointestinal degradation. In 2009, the FDA approved OralLyn, an insulin spray, conditionally under its Investigational New Drug (IND) program, for patients with type 1 and type 2 diabetes who are suffering from serious or life-threatening diabetes, who have no satisfactory alternative treatments and who are not eligible for participation in the phase 3 clinical trial of the drug. The spray delivers prandial insulin through a device that sprays insulin on the cheek; however, only 10% of the insulin delivered is absorbed (45). A new buccal system is currently under development; it aims to deliver insulin using a small film with fixed thickness and shape and might be particularly useful in psychiatric and geriatric patients due to its ease of use, its tastelessness and its quick-dissolution properties (46). Transdermal The skin is the largest organ of the body that allows absorption of insulin into the blood stream with avoidance of gastrointestinal degradation. The dermis has a rich blood supply, in contrast to the relatively poorly vascularized subcutaneous tissue currently used. Transdermal insulin is painless and allows for easy handling by patients. Although intact skin is an effective barrier for the body with low permeability that prevents the passage of insulin, several technologies have been employed to overcome this barrier, and some of them are now already in clinical trials or on the market. Microneedles combined with drug patches are a system involving tiny needles with a mean diameter of 1 μm (micron) and a length range of 1 to 100 μm. Microneedles pierce the skin openings into microchannels to allow the transport of insulin through the skin. Because they penetrate only down to the stratum corneum due to their microsize, nerve endings are not reached and, therefore, no pain is elicited (47). Currently, a device employing this technology called V-Go, which delivers a continuous preset basal rate of insulin (20, 30 or 40 units of insulin in a 24-hour period) and allows on-demand bolus dosing at mealtimes has already been approved by the FDA for use in patients with type 2 diabetes. This device is compatible with both aspart and lispro (48). Phospholipid insulin-containing vesicles, which are elastic, flexible and deformable and allow for squeezing into the pores of skin, are another technology currently being examined (49). Last, iontophoresis, a technique that employs small electric currents for enhancing the skin’s permeability to accept insulin, is currently being
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tested in animal studies. In rats, iontophoresis drove the insulinloaded nanovesicles into the deep layers of the skin, which allowed the release and gradual absorption of insulin (50). Oral Insulin administered orally has the potential to be taken up by the gastrointestinal tract, delivered to the portal vein and transported directly to the liver, mimicking the pathway of endogenous insulin and producing a physiologic hepatic-to-peripheral insulin gradient. However, insulin is not lipophilic and has a large molecular weight, making it hard to be absorbed. As well, enzymatic degradation in the stomach, inactivation by gastric acid, digestion by enzymes in the intestinal lumen and poor permeability across the intestinal epithelium all contribute to the low oral bioavailability of oral insulin preparations. Newly devised strategies, such as enteric coated tablets, absorption enhancers, enzyme inhibitors, insulin chemical modifications and special carriers are now being studied with the hope of increasing the oral bioavailability of insulin (51).
Conclusions In summary, a large number of novel insulin molecules, preparations and delivery systems are being developed as tools to improve the management of type 2 diabetes, with the ultimate goal of reducing the burden of diabetes for individuals, improving health and reducing morbidity and mortality. Some of these approaches, particularly the new basal insulins, such as Gla-300, degludec and peglispro, seem to have particular benefits for patients experiencing, or at risk for, frequent hypoglycemia based on consistent reductions of hypoglycemia, as demonstrated in phase 3 clinical trials. The availability of more concentrated insulin preparations (U-200, U-300) may have benefits because of improved pharmacokinetics, but they also may be particularly useful in improving patient comfort and acceptance, particularly in individuals with very high insulin requirements. The potentials for new routes of insulin delivery are intriguing, but it remains to be seen whether the stated preference to avoid injections will translate into a preference of prescribers and users to use these alternative agents, given the relatively low uptake of inhaled insulin thus far. A further common but major hurdle will be the willingness of payers to reimburse novel therapies. Novel insulin products are generally required to demonstrate equivalent (noninferiority) glycemic control potential, and because most pharmacoeconomic models are based heavily on reduction of A1C levels for prevention of complications and may not include or adequately estimate the costs of hypoglycemia, it may be difficult to demonstrate cost-effectiveness. Patient-reported outcomes and quality-of-life studies may become more important as tools to assess the advantages of newer products. The capacity of physicians to individualize care with insulin is now greater than ever because of these emerging insulins and delivery strategies. The increasing numbers of options for insulin therapy, together with the growth in oral and injectable antihyperglycemic agents, are challenging for physicians and healthcare professionals working to care for patients with diabetes. No matter how many options there are, efficacy, side-effect profile, patient preference and cost-effectiveness should remain the cornerstones when deciding on treatment regimens.
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