Basal insulin therapy: unmet medical needs in ... - Wiley Online Library

DR. CHIH YUAN WANG (Orcid ID : 0000-0002-6742-3935)

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PROF. WAYNE H-H SHEU (Orcid ID : 0000-0002-8805-8340)

Article type

: Review

Title Page Manuscript type: Review article

Title: Basal insulin therapy: unmet medical needs in Asia and the new insulin glargine in diabetes treatment

Authors: Kai-Jen Tien1, Yi-Jen Hung2, Jung-Fu Chen3, Ching-Chu Chen4,12, Chih-Yuan Wang5, Chii-Min Hwu6, Yu-Yao Huang7, Pi-Jung Hsiao8, Shih-Te Tu9, Chao-Hung Wang10, Wayne Huey-Herng Sheu11,*

Affiliation: 1.

2.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan Tri-Service General Hospital, Song-Shan branch, Taipei, Taiwan

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jdi.12984 This article is protected by copyright. All rights reserved.

3.

Division of Metabolism, Department of Internal Medicine, Kaohsiung Chang Gung

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Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 4.

5.

6.

7.

8.

9.

Division of Endocrinology and Metabolism, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan City, Taiwan Divisions of Endocrinology and Metabolism Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Departments of Internal Medicine College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan

10. Division of Endocrinology and Metabolism, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan

11. Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

12. School of Chinese Medicine, China Medical University, Taichung, Taiwan

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*Correspondence: Wayne Huey-Herng Sheu, Taichung Veterans General Hospital, #1650,

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Sec. 4, Taiwan Boulevard, Taichung 407, Taiwan. Tel: +886 4 2359 2525 Fax: +886 4 2374 1318 Email: [email protected]

Running title: New insulin glargine for Asian diabetes

Abstract Diabetes remains a global epidemic problem and a tremendous health challenge especially in Asian population. Dramatic increases in the prevalence of diabetes across different countries or areas in Asia have been reported in recent epidemiological studies. While clinical guidelines have strengthen appropriate anti-hyperglycaemic medications and lifestyle modifications for optimal diabetes management, inadequate glycaemic control still occurs in many patients with an increased risk of developing microvascular and macrovascular complications. Insulin administration is the main therapy for diabetes in response to the inability of insulin secretion, and is recommended in current guidelines to treat patients with type 2 diabetes (T2D) after failure on oral anti-diabetic drugs (OADs). Clinical studies have revealed that long-acting insulin analogues improve basal glyacemic control with reduced risk of hypoglyacemia. In this review, we discuss previous challenges with basal insulin therapy in Asia, the pharmacological development of insulin analogues to overcome the unmet medical needs, and recent clinical studies of the new ultra-long acting insulin analogue, insulin glargine U300 (Gla-300). Moreover, relevant findings of current real-world evidence are also included for the comparison of efficacy and safety of different insulin formulations. Based on the accumulating evidence showing low incidence of hypoglyacemia and technical benefits of dose titration, treatment of Gla-300 can be a promising strategy for Asian diabetic patients to achieve glyacemic target with favorable safety. This article is protected by copyright. All rights reserved.

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Keywords: basal insulin therapy, diabetes, insulin glargine, Asians, hypoglyacemia

Introduction Prevalence of diabetes mellitus has continuously increased worldwide1,2. There are two main types of diabetes, type 1 diabetes (T1D, formerly called insulin-dependent diabetes) and type 2 diabetes (T2D, formerly called non-insulin-dependent diabetes). T2D is more common in adults and constitutes the majority (90-95%) of all diabetes cases3. Epidemiologic studies estimate that globally the number of diabetic patients is expected to rise from 415 million in 2015 to 642 million by 20404. Diabetes is considered as a serious public health challenge in developing countries following the epidemiologic transition5. Asia has become the epicenter of the current diabetes epidemic after having undergone drastic socioeconomic changes in the past decades. In Asian populations, particularly East Asians, diabetes tends to develop at a younger age and a lower body-mass index (BMI) with the characteristic of visceral obesity5,6. Under the influence of nutrition transition, rapid urbanization and increased adoption of Western lifestyles, Asian patients have accounted for 60% of the world’s diabetic population. In 1980, less than 1% of Chinese adults had the disease; and by 2008, the prevalence had soared to nearly 10%7. A Taiwanese study also demonstrates an upward trend in the T2D prevalence during 2000-2007 in adults in Taiwan8. China and India are projected to be among the top 10 countries in the world with the highest number of estimated cases by 20409,10.

Diabetes can develop acute and chronic complications in response to inadequate glycaemic control. The former includes hypoglycaemia diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS)11, and the latter occurs mainly due to a mix of microangiopathy


(causing nephropathy, neuropathy, and retinopathy) and macrovascular disease (causing

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stroke, coronary heart disease, and peripheral vascular disease)12. The long-term health problems have a significant impact on quality of life and increase the risk of premature death, posing a heavy economic and social burden in all nations13. Early intervention to achieve and maintain glycaemic control is essential to reduce the risk of diabetes‐ related chronic complications14. However, despite the evidence for the benefit of optimal glycaemic control, there are many individuals in Asia whose diabetes remains uncontrolled15. For example, previous studies reported that less than 40% of diabetic patients achieved adequate glycaemic control in China and Taiwan after treatment16,17. This review article points out the unmet medical needs of diabetes treatment as well as the existing clinical challenges associated with basal insulin therapy in Asia, and brings the new generation basal insulin into the scope for effective glyacemic control with better blood glucose stability, improved tolerability and convenience advantages.

Insulin therapy for diabetes Diabetes management requires appropriate glycaemic control to prevent acute and chronic complications associated with the disease14,18. Measurement of glycated hemoglobin, predominantly HbA1c, is integral to the management of diabetes15. The HbA1c level reflects a combined exposure to both FPG and PPG19, which can be used as an indicator of long-term glycaemic control and a basis for adjustment of diabetes treatment plans20. Current treatment guidelines often recommend that patients achieve and maintain an HbA1c level that is lower than 7%21. An ideal range or target HbA1c level may vary from person to person, depending on the clinical and demographic characteristics of the individual patient, such as age and gender20. To minimize the risk of long-term vascular complications, NICE (the National


Institute for Health and Care Excellence) has recommended a tighter target level of 6.5% or

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lower in adult patients with T1D22. AACE/ACE (American Association of Clinical Endocrinologists and American College of Endocrinology) also recommended an HbA1c target of less than 6.5% for adult patients with recent T2D onset and no clinically significant CVD23. In addition, JDS (Japan Diabetes Society) set the main objective value of HbA1c to less than 7% for patients with diabetes to prevent microvascular complications24.

Insulin is the mainstay of therapy for T1D patients due to insulin deficiency25. Almost all people with T1D should be treated with multiple-dose insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII). In patients choosing MDI, it is the current standard of care to use long-acting basal insulin analogues1. For T2D patients, most of them should begin with diet and lifestyle changes. When these modification efforts do not achieve or maintain glycaemic targets, metformin is usually the preferred initial pharmacological agent25,26. Although insulin is the most potent agent against hyperglycemia, it is still applied to T2D patients in response to elevated glycated hemoglobin (HbA1c) after failure on oral anti-diabetic drugs (OADs)18,27. Owing to the progressive loss of pancreatic β-cell function in T2D, insulin therapy is eventually indicated for most patients25.

Basal insulin therapy following metformin treatment was recommended in clinical guidelines, such as 2015 ADA/EASD (American Diabetes Association/European Association for the Study of Diabetes) guidelines, 2018 ADA standards of medical care in diabetes, and 2018 AACE/ACE consensus statement for T2D managemnet18,23,28. In Taiwan, taking effect on nowadays, the health insurance authorities agree that insulin could be considered for T2D treatment at an early stage29. The injected basal insulin alone is the most convenient initial This article is protected by copyright. All rights reserved.

regimen to supplement a patient’s endogenous basal insulin level, which can be used in

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combination with metformin and sometimes an additional noninsulin agent. If HbA1c remains uncontrolled despite normalization of the FPG, we could consider proceeding to the combination of injectable therapy to address PPG excursions. Options include the addition of one injection of a rapid-acting insulin analogue administered before the largest meal, or a glucagon-like peptide 1 (GLP-1) receptor agonist. Recent research showed that combining GLP-1 receptor agonists with basal insulin demonstrated comparable or slightly better efficacy versus the addition of prandial insulin, with less hypoglycaemia and no weight gain25,30. As an alternative, in selected patients, a simpler but somewhat less flexible approach is transitioning from basal insulin to premixed formulations containing an intermediate or long‐ acting basal insulin mixed with short/rapid-acting prandial insulins in fixed ratios26,31. If patients still do not respond adequately to these regimens, the basal-bolus strategy, which adds more than two rapid-acting insulin injections before meals to basal insulin, may be required32. Dose titration is important once an insulin regimen is initiated. Adjustments should be made in both mealtime and basal insulins based on the prevailing blood glucose levels and an understanding of the pharmacodynamic profile of each formulation25.

Challenges with basal insulin therapy in Asia Although comprehensive guidelines for the treatment of T2D patients emphasized the importance of glycaemic control with appropriate anti-hyperglycaemic medications and lifestyle modifications, inadequate glycaemic control still occurs in many patients due to the delayed insulin initiation or intensification33,34. A retrospective longitudinal analysis of 40,627 T2D patients from 5 European countries and the USA revealed poor glycaemic control in patients initiating basal insulin35. It was found that the proportion of patients for


short-term and long-term optimal glycaemic control increased after the initiation of basal

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insulins with or without OADs. However, almost half of the patients in France, Italy and Spain, and 62.9% of the patients in the UK, initiated basal insulin with very high HbA1c levels (>9.0%), and more than 70% of patients still failed to reach HbA1c target (≤7.0%) in the first 3 months and 2 years after the insulin therapy. About 9% of patients reported hypoglyacemia experiences according to the electronic medical records35.

The issue of delayed insulin therapy also exists in Asian countries. The First Basal Insulin Evaluation (FINE) Asia study, a prospective, observational registry follow-up study conducted in 11 Asian countries, was carried out to evaluate the initiation of basal insulins (neutral protamine Hagedorn (NPH) insulin, glargine, or detemir) in patients with T2D inadequately controlled by OADs. This study showed that in a real-world setting insulin initiation is delayed in Asian patients by approximately 9 years36. The efficacy and safety of basal insulin therapy by country was further investigated and the results revealed large variation of glycaemic control in T2D patients among the country cohorts37. Nevertheless, T2D patients in Korea and Taiwan represented the smallest reduction in HbA1c and the lowest proportion of patients reaching the treatment goals of HbA1c and FPG, which was closely correlated to a delay of insulin initiation with the prolonged OAD use (9.2 and 11.1 years, respectively) after diabetes more than 10 years. In addition, hypoglycaemia rates also varied in different countries, which patients of 7.1% (India) to 27.3% (China) had experienced hypoglyacemia at least once37.

According to a Taiwanese study comprising 836 patients with poorly controlled T2D (duration of diabetes: 11.6 ± 7.0 years; duration of OAD therapy: 10.7 ± 6.6 years), the mean HbA1c value had reached as high as 10.1% when basal insulin therapy was initiated. Most of


the patients were insulin-naïve, with just only 6.9% of them having received insulin therapy

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before participation. In this study, glycaemic control was significantly improved, after the treatment of basal insulin for 6 months, with reductions in both HbA1c and FPG38. An earlier Japanese study found that 83.4% of the Japanese patients had microvascular complications at the time of initiating insulin treatment39. In a sub-group analysis of observational, non-interventional ALOHA (Add-on Lantus® to Oral Hypoglycemic Agents) study, Japanese insulin-naïve patients without microvascular complications showed better response to basal supported oral therapy with higher chances of achieving HbA1c < 7.0% than those with complications40.

Technical difficulty of insulin therapy, such as subcutaneous injection, dose titration, and regular SMBG, may affect patients’ willingness to accept insulin therapy38. Once insulin therapy is initiated, dose titration should be taken into account to achieve optimal glyacemic control. Real-world evidence from ORBIT (Observational Registry of Basal Insulin Treatment) study indicated the initiation of basal insulins was delayed in the majority of patients with T2D in China41. A suboptimal titration of basal insulins was also demonstrated, as Asian patients with diabetes may have delayed insulin initiation and higher risk in hypoglycemia. Such ethnic and genetic differences between Asians and Caucasians may cause a clinical challenge to deal with the dose adjustment for different insulin needs42,43. Moreover, it was found that one-quarter of T2D patients treated with basal insulin had difficulties attaining the recommended HbA1c goal despite adequate FPG levels44. In that case, further interventions to control PPG may become necessary with the introduction of rapid-acting bolus (mealtime) insulin in a basal-bolus regimen or GLP-1 receptor agonist. For patients with T1D, multiple injections of mealtime insulin are also needed. Moreover, patients may be required to calculate the mealtime insulin doses to match the amount of


carbohydrate in the meal45. Maintenance of glyacemic control thereby can be achieved by

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intensification of insulin therapy, either adding another type of insulin or increasing the number of injections per day. However, the additional task could make insulin therapy particularly more cumbersome and greater injection frequency may restrict patients’ daily activities with a negative impact on quality of life46,47.

Hypoglycaemia is widely regarded as a critical barrier to insulin therapy initiation and adherence 48-50. Hypoglycaemia is associated with acute short-term symptoms related to either glucose counter-regulatory responses, such as tachycardia and shakiness, or to neuroglycopenia, such as irritability, confusion, and in severe cases that may lead to increased mortality51. Repeated hypoglycaemia may reduce working capacity and quality of life, increase a fear of recurrent hypoglcaemic episodes with insulin therapy, and eventually result in deterioration of glycaemia control51. In a Taiwan’s nationwide population-based study, symptomatic hypoglycemia was found strongly associated with major cardiovascular events that increased hospitalization and all-cause mortality52. Nocturnal hypoglycaemia is likely to be underreported because patients may not awaken or recognize the symptoms during sleep53,54. Severe hypoglycaemia is recognized as one of the strongest predictors of macrovascular events in patients with T1D and T2D, which was also noted by the studies from Taiwan and Japan55-57. The increased risk of cardiovascular diseases is associated with long-term hypoglycaemia, either as a result of weight gain related to defensive food intake, or through activation of the sympathoadrenal response51,55. According to the ACCORD study, intensive glycaemia control increased the occurrence of severe hypoglcaemia in T2D patients at high risk of cardiovascular events, but may not directly account for the increased death58. However, improved glycaemic control for long-term, which was investigated in the CREDIT study over 4 years, facilitated the reduction of cardiovascular events59.


Another barrier to insulin therapy is glycaemic variability60. Variable glucose readings

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generate difficulties to adjust insulin dosage. Furthermore, the variability in glucose levels is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. The scope for insulin-induced glucose variability is particularly great with basal insulin because of its prolonged absorption resulting from high-dose subcutaneous depots61. While rapid/short-acting insulin may reduce postmeal glucose excursions in multiple daily injection (MDI)62, as will be pointed out later, long-acting insulin analogues can more effectively mimic the constitutive secretion of endogenous insulin than neutral protamine Hagedorn (NPH), the conventional basal insulin, thereby reducing glycaemic variability34,63.

Tackling barriers to insulin therapy The goal of effective insulin therapy for diabetes patients is to mimic the normal insulin secretion in order to achieve tight glycaemic control without the risk of hypoglycaemia26,34. Various approaches have been made to develop insulin analogues with different PK/PD profiles, including basal and ultra-long-acting basal insulins (Figure 1)64,65. NPH insulin was originally produced in 1946, which could be mixed with soluble insulin and became the predominant basal insulin in clinical use throughout 20th century64,66. As an intermediate-acting formulation, NPH displays time-action profiles that differ considerably from the physiological dynamics of endogenous basal insulin secretion.

The advent of recombinant DNA technology in the 1980s enabled optimization of the properties of insulin via modification of the amino acid sequence67. New long-acting insulin analogues, such as glargine and detemir, showed fairly flat PK profiles, a duration lasting more than 24 hrs, and little day-to-day variation, thus allowing once-daily dosing68. The first


long-acting basal insulin analogue to be approved for clinical use was insulin glargine 100

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units/mL (Gla-100), and it is usually administered as a once-daily subcutaneous injection in the evening69. The pharmacological characteristics of insulin glargine have made substantial achievement of more physiological basal glycaemic control with reduced risk of hypoglycaemia than current intermediate-and long-acting insulin preparations70-73.

While the mean PK/PD and variability proﬁles of Gla-100 represent substantial improvements, it still does not completely mimic physiological insulin secretion64. Administration of high dose Gla-100 may show a peak on the PK/ PD profile74. On the other hand, a low dose may not be sufficient to last a 24-hour period, and there is still intra- or inter-individual variations following injections75. To address these limitations, ultra-long-acting basal insulin regimens were developed, such as insulin glargine U300 (Gla-300) and insulin degludec, to provide comparable efficacy reaching glycemic target with less body weight gain and reduced hypoglycaemia76. Gla-300 is a three times more concentrated formulation as compared to Gla-100, which is designed for once-daily administration. Injection of Gla-300 leads to the formation of a smaller subcutaneous depot, resulting in a distinct PK profile with more consistent and prolonged insulin release77. Consequently, glucose control can remain up to 36 hours after administration, resulting in decreased hypoglycaemic episodes (overall and nocturnal) in patients78.

Clinical studies and real-world evidence of insulin glargine U300 The clinical efficacy of Gla-300 was evaluated in six Phase III, multicentre, randomized, open-label, parallel-group, 6-month clinical trials known as the EDITION series (Table 1). The EDITION 1, 2 and 3 trials recruited patients with T2D79-82, and the EDITION 4 trial


patients with T1D83. EDITION JP1 and EDITION JP2 were conducted in Japanese patients

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with T1D and T2D, respectively84,85.

EDITION 1 and 2 are studies related to regimen switching. T2D patients who had inadequate glycaemic control on basal and mealtime insulin (EDITION 1) or basal insulin and OADs (EDITION 2) were randomly allocated to either the Gla-300 or the Gla-100 group. The results showed that Gla-300 controlled HbA1c as well as Gla-100, with a consistently lower risk of nocturnal hypoglycaemia (EDITION 1), or a lower risk of hypoglycaemia during the night and at any time of the day (EDITION 2)79,80. EDITION 3 was conducted in treatment of insulin naïve T2D patients, the results being comparable to EDITION 1 and 281. Extended follow-up of the EDITION 3 participants revealed that the efficacy of Gla-300 was maintained over 12 months82. Moreover, it was noted in EDITION 2 and 3 that patients treated with Gla-300 consistently appeared to have less blood glucose variability and lower risk in symptomatic and severe hypoglyacemia, confirmed by Low Blood Glucose Index (LBGI)82,86,87. In T1D patients with long disease duration, EDITION 4 showed that Gla-300 achieved glucose control comparable to Gla-100, with a lower risk of hypoglycaemia after transfer from other insulin regimens, irrespective of time of injection, and with less weight gain83.

EDITION JP 1 and 2 were Asian studies, their results suggesting racial differences in efficacy and safety of Gla-300 were not an issue. Glycaemic control did not differ between Gla-300 and Gla-100, but there were fewer hypoglycaemic episodes at any time of the day observed with Gla-300 in Japanese T1D patients pretreated with basal plus mealtime insulin (EDITION JP 1) or in Japanese T2D patients pretreated with basal insulin plus OADs This article is protected by copyright. All rights reserved.

(EDITION JP 2)84,85. In particular, it was clinically relevant that the use of Gla-300 in

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Japanese patients with T1D/T2D was associated with a lower risk of nocturnal hypoglyacemia during the treatment of 6 months, including the first 8 weeks that titration of basal insulin was often required.

A meta-analysis of EDITION 1, 2 and 3 provides a comparison of the 6-month safety and efficacy profiles of Gla-300 and Gla-100 in a broader patient population with T2D88. The mean change in HbA1c for Gla-300 was comparable to that for Gla-100. Annualized rates of confirmed (≤3.9 mmol/L,