Can J Diabetes 39 (2015) S160–S166
Contents lists available at ScienceDirect
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
K.T. Cheung, P.A. Senior / Can J Diabetes 39 (2015) S160–S166
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,
S161
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
S162
K.T. Cheung, P.A. Senior / Can J Diabetes 39 (2015) S160–S166
(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
Contents lists available at ScienceDirect
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
K.T. Cheung, P.A. Senior / Can J Diabetes 39 (2015) S160–S166
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,
S161
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
S162
K.T. Cheung, P.A. Senior / Can J Diabetes 39 (2015) S160–S166
(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
