Optimizing Glycemic Control Through Titration of Insulin Glargine 100 U/mL: A Review of Current and Future Approaches with a Focus on Asian Populations

Asians show a strong ethnic association and genetic predisposition for developing type 2 diabetes mellitus (T2DM) at a younger age, and a lower body mass index than their Caucasian counterparts [1‐3]. Consequently, Asian populations demonstrate higher rates of morbidity and early mortality [4, 5]. Only 37.3% of Asian patients from the International Diabetes Management Practice Study (IDMPS) [6] and 35.3% from the Joint Asia Diabetes Evaluation (JADE) program [7] had adequately controlled T2DM, with glycated hemoglobin (HbA_1c) levels < 7%, as recommended by the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) [8, 9].

T2DM is a progressive disease, and early treatment intensification has been shown to aid in the achievement of glycemic targets [6, 7, 10‐12]. Benefits of intensive glycemic control include a reduction in the risk of microvascular complications and the impact of macrovascular problems [13, 14]. Studies have illustrated that patients on basal insulin are often able to achieve HbA_1c < 7% [15‐17], and early intervention with basal insulin has been shown to maintain glycemic control in the long term [10]. Evidence, therefore, indicates that early initiation of basal insulin should be considered for patients with T2DM.

However, data indicate that Asian patients are poorly controlled for approximately 6–10 years, with average HbA_1c levels of 8.7–9.8% at the point of basal insulin initiation [11, 18‐20]. The prospective, observational First Basal Insulin Evaluation (FINE) study examined the initiation of basal insulin in insulin-naïve patients with T2DM, uncontrolled (HbA_1c ≥ 8%) with oral antidiabetic drugs (OADs), in real-world clinical practice from 11 different Asian countries [19]. The study showed that in countries where the delay in initiation of basal insulin was > 9 years, patients were less likely to reduce their HbA_1c levels and meet glycemic targets [21]. Also of interest is a pooled analysis of 724 Asian patients for whom data were extracted from seven randomized clinical trials (RCTs) that investigated the initiation and titration of insulin glargine 100 U/mL (Gla-100). The pooled analysis demonstrated, through multivariate analysis, that a higher baseline HbA_1c at initiation of treatment with Gla-100 is associated with a smaller reduction in HbA_1c (p < 0.0001) [22]. This finding reinforces the importance of early initiation of basal insulin in Asian patients.

Once basal insulin is initiated, dose titration is an important factor affecting the patient’s ability to achieve their target glycemic control [23]. Several studies have demonstrated the attainment of HbA_1c levels < 7% in patients with T2DM titrating Gla-100 toward well-defined physiologic targets, known as the treat-to-target (TTT) method [16, 17, 24‐26].

There is a difference in insulin needs between Asian and Caucasian populations on account of ethnic and genetic differences, as demonstrated by a pooled analysis of 16 RCTs [1]. In this analysis, at similar doses of Gla-100, non-Asian patients were able to achieve better HbA_1c control than Asian patients, indicating that higher daily basal insulin doses may be required by Asian patients to achieve adequate glycemic control [1]. Differences in the pathophysiology of T2DM mean that the findings from clinical trials in Caucasian populations cannot necessarily be extrapolated to Asian populations, as noted in a publication where this was cited to be one of the potential reasons for insufficient dose adjustments in Japanese patients with T2DM [27]. Additionally, there is a lack of data on the titration of basal insulin in Asian populations compared with that available for Caucasian populations.

Asian patients with diabetes are generally leaner than Caucasian patients and are therefore perceived to have an increased risk of hypoglycemia (although this has been demonstrated to be an incorrect assumption [1]), which leads to conservative treatment goals [28] and a cautious approach to the titration of insulin in Asia [19]. Real-world data from the Observational Registry of Basal Insulin Treatment (ORBIT) study conducted in China demonstrates suboptimal titration of basal insulin [29]. In the study, titration of basal insulin was in accordance with the provider’s recommendation and the patient’s willingness [20], and the dose of basal insulin was increased by only 0.03 units/kg/day over a period of 6 months [29].

These challenges demonstrate the difficulty of managing dose titration in Asian patients (a possible reason for the inadequate glycemic control seen amongst Asians), and highlight the need for further education and examination of the titration of basal insulin in Asia.

Of the several basal insulin analogs available, this review will focus on Gla-100 (Lantus^®, Sanofi, France), a long-acting recombinant human insulin analog indicated for the treatment of adults and pediatric patients with type 1 diabetes mellitus, and adults with T2DM [30]. Newer basal insulin analogs, such as insulin glargine 300 U/mL (Gla-300), will not be discussed in this review. Gla-100, by virtue of having been available for more than 10 years [30, 31], has amassed a large volume of RCT and real-world data that warrants standalone discussion, especially since titration is still suboptimal in Asia [19, 29]. Despite the availability of newer basal insulins, in the opinion of the authors Gla-100 remains an integral part of the diabetes treatment paradigm in Asia, and discussion of approaches to the titration of Gla-100 is therefore still relevant. In this review, global and—where possible—Asian data on the efficacy and safety of titrating Gla-100 will be explored, and opinion on these data from the authors and their experiences with treating T2DM in Asian patients are also included. Where possible, approaches specific to the titration of Gla-100 have been reviewed; however, due to the lack of data, approaches to the titration of other basal insulins have also been included. This article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

Meta-analyses published in 2014 by DeVries et al. [32] and Owens et al. [33] examined efficacy and safety outcomes across 15 TTT trials with once-daily Gla-100 added to different combinations of OADs at bedtime in insulin-naïve individuals with T2DM uncontrolled on OADs. The analysis included data derived from Sanofi-sponsored phase IIIb and IV TTT RCTs with protocol-driven titration algorithms for a duration ≥ 24 weeks [32, 33]. Overall, 2837 patients were analyzed, with efficacy assessed in terms of reduction in HbA_1c and fasting plasma glucose (FPG) [32, 33]. Safety outcomes assessed included hypoglycemia, as well as change in insulin dose and body weight [32, 33]. Safety and efficacy outcomes were calculated for weeks 0–12, referred to as the “titration period,” as well as for weeks 12–24, referred to as the “maintenance period” [33]. All outcomes were assessed for each of the different treatment combinations, which included Gla-100 with metformin, Gla-100 with sulfonylurea, as well as Gla-100 in combination with metformin and sulfonylurea [32, 33].

Glycemic control improved following the initiation and subsequent titration of Gla-100, with HbA_1c and FPG decreasing from baseline to week 12, and this decrease was sustained or further improved at week 24 in participants receiving all three treatment combinations [32, 33]. The combination of Gla-100 and metformin demonstrated the greatest efficacy, with a mean reduction in HbA_1c from 8.7% at baseline to 7% at week 24 [32]. Of the patients receiving Gla-100 and metformin, 56.8% achieved an HbA_1c target of < 7.0% at week 24, the largest proportion of patients amongst the three treatment combinations [32]. Of the total HbA_1c reduction achieved at week 24, > 80% was achieved by week 12, demonstrating that Gla-100 can aid in the achievement of early and satisfactory treatment outcomes [33].

With regard to the safety outcomes, the combination of Gla-100 and metformin demonstrated the lowest incidence of overall, daytime, and nocturnal hypoglycemia, as well as the lowest weight gain compared with the other treatment groups [32, 33]. This was despite the greatest increase in the insulin dose taken by those on Gla-100 and metformin compared with patients who received sulfonylurea in their treatment regimen [32, 33]. The incidence of hypoglycemia was similar during the titration and maintenance periods for all of the treatment groups [33].

Overall, the meta-analyses concluded that initiation and subsequent titration of Gla-100 can lead to improved early (> 80% reduction in HbA_1c by week 12) and sustained glycemic control, with a low incidence of hypoglycemic events and minimal changes in weight [32, 33]. Patients receiving Gla-100 and metformin had a significantly shorter duration of diabetes at initiation compared with patients who received sulfonylurea in their treatment regimen—a possible reason for the greater efficacy and safety outcomes achieved by these individuals [32, 33].

In the past decade, several clinical trials have applied and investigated uniform titration algorithms, often referred to as TTT algorithms [34, 35]. TTT is a therapeutic concept that takes into consideration and works toward well-defined and specific physiological targets for controlling the pathophysiology of a disease [35]. The TTT approach is particularly suitable for the treatment of diabetes, as it can be measured by “gold-standard” quantitative measures such as HbA_1c and fasting blood glucose (FBG), clinical thresholds which have been determined by multiple international and national diabetes organizations [35]. Multiple TTT algorithms have been investigated in clinical studies. These algorithms are designed to produce equal degrees of glycemic control and are therefore able to reveal differences in safety, tolerability, and clinical utility between different treatment regimens when insulin dosing and efficacy is maximized [36]. An overview and the intervention details of several key TTT clinical trials involving patients with T2DM with inadequate glycemic control on OADs alone are shown in Table S1 in the Electronic supplementary material (ESM). The studies listed show consistent and substantial improvements in glycemic control, as well as a low incidence of hypoglycemic episodes with Gla-100.

It is often considered too difficult and time-consuming for those in a primary care environment to initiate patients with T2DM on basal insulin [34, 37]. A primary care physician has an average consultation time of 5–20 min to oversee and assess the large amount of clinical information that must be reviewed before initiating and titrating basal insulin for each individual patient [38]. Various approaches to the titration of Gla-100 and other basal insulins, using TTT algorithms, have been investigated in order to help improve this situation. Some of those that have been investigated in clinical studies are discussed below, and others will be highlighted in the section “Strategies for optimal titration of basal insulin in Asian populations.”

Recommendations on the initiation and titration of basal insulin can be found in several international clinical practice guidelines. The 2017 American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management algorithm specifies that basal insulin can be initiated in patients with T2DM with an entry HbA_1c level < 7.5% when either monotherapy with metformin or other OADs, or dual therapy with metformin and other agents, fails to achieve the glycemic target (HbA_1c < 7%) [63]. The guidelines also indicate that basal insulin can be initiated as a part of dual therapy with metformin in patients with entry HbA_1c ≥ 7.5%, or when a patient presents with a HbA_1c level > 9.0% (dual or triple therapy with metformin) and symptomatic hyperglycemia at entry [63]. The 2015 diabetes clinical practice guidelines from the AACE/ACE acknowledged that the traditional postponement of insulin therapy after prolonged failure of lifestyle management and OADs to achieve glycemic control has been revised in the past decade, and recommended that basal insulin therapy should be initiated much sooner, and often in combination with OADs [64]. The ADA’s updated Standards of Medical Care in Diabetes 2017 states the importance of dose titration of any insulin regimen once initiated, and that dose adjustments should be based on prevailing BG levels, together with knowledge of the pharmacodynamic profile of the insulin used [23]. The ADA recommends that if the HbA_1c target (< 7%) is not achieved after 3 months of monotherapy with metformin, combination therapy of basal insulin with metformin, amongst other options, should be considered [23]. The 2015 position statement from the ADA/EASD emphasizes that insulin has the advantage of being effective where other agents may not be, and should be considered a part of any combination regimen when hyperglycemia is severe, particularly if the patient is symptomatic [9]. The International Diabetes Federation (IDF) recommends the initiation of basal insulin after the failure of combination therapy with metformin and other OADs, and the titration of insulin using a self-titration regimen, or with at least biweekly contact with a HCP [65]. Table 1 highlights key recommendations regarding the initiation and titration of basal insulin from several international guidelines.

Most countries in Asia have developed diabetes treatment guidelines that closely reflect international guidelines. For example, recommendations in the 2015 Indonesian Clinical Practice Guideline of Insulin Therapy in Diabetes Mellitus Patients reflect guidelines issued by the ADA/EASD and AACE/ACE, and contain guidance on the initiation and titration of insulin [66]. Recommendations from Hong Kong’s Department of Health regarding the treatment of hypergylcemia in primary care settings also closely follow guidelines from the ADA/EASD, AACE/ACE and IDF, amongst others, with different treatment options for different baseline HbA_1c levels, as well as information on the titration of insulin [67]. The Philippine Practice Guidelines on the Diagnosis and Management of Diabetes Mellitus are aimed at educating all physicians involved in the management of diabetes. The guidelines include recommendations on the screening and diagnosis of diabetes mellitus, the screening and prevention of complications associated with diabetes, as well as information on the management of diabetes, particularly for special populations such as the elderly [68]. In Malaysia, the Ministry of Health’s endocrinologists developed a practical guide for insulin therapy in 2010 that outlines a clear and concise approach for all HCPs to initiate insulin safely, optimize doses effectively, and intensify insulin regimens promptly [69]. The release of the guidelines was followed by nationwide education on the guidelines for primary care physicians, the result of which was an increase in the rates of insulin initiation in primary care practice. The Clinical Practice Guidelines for Diabetes Care 2015 from the Diabetes Association of the Republic of China (Taiwan) emphasizes that treatment goals should be individualized based on the patient’s condition, similar to recommendations from the 2015 ADA/EASD position statement [70]. The 2014 Clinical Practice Guideline for Diabetes from Thailand was adapted from the IDF, ADA/EASD, and the National Institute for Health and Care Excellence (NICE) guidelines, and recommends starting basal insulin in patients with T2DM after the failure of dual or triple therapy with OADs [71]. Table 2 provides an overview of key recommendations regarding the initiation and titration of basal insulin from several Asian-country-specific guidelines.

In alignment with international guidelines, the majority of the recommended titration algorithms in Asia follow the TTT approach (Table 2), wherein basal insulin is initiated at a low dose to avoid hypoglycemia and subsequently adjusted based on pre-defined physiologic targets, meaning that patients may eventually end up on different doses of insulin. The TTT approach has proven to be an effective approach for initiating and adjusting the dose of basal insulin for non-Asian and Asian patients with T2DM [16‐18, 32, 33, 39].

Based on their clinical experience, the authors have provided recommendations for the initiation and titration of basal insulin specific to the Asian population in Fig. 1 and Table 3, respectively.

The algorithm in Fig. 1 is in accordance with those provided by the ADA, AACE/ACE, and IDF [23, 63, 65], and indicates the optimal time for initiation of basal insulin; namely, following failure of treatment with metformin along with lifestyle modifications for a period of 3 months. However, the reality is that this algorithm is often not followed in clinical practice in Asia. In the authors’ clinical experience, basal insulin is often initiated following failure with dual or triple OAD therapy (in addition to lifestyle modifications). Although patient-specific factors must be taken into consideration, in general there needs to be a push for earlier initiation of basal insulin in Asia, and the authors hope to encourage this.

The titration algorithm in Table 3 is closely aligned with other algorithms given in Asian-country-specific guidelines [66, 67, 69, 71], and involves a low dose of basal insulin for initiation to avoid hypoglycemia, and subsequent dose adjustments based on predefined physiologic targets; that is, the TTT approach. When choosing this algorithm, it is important that other patient- and disease-specific factors are also taken into consideration, as well as any dose adjustments to OADs that might be required.

Consistent and substantial improvements in glycemic control, as well as a low incidence of hypoglycemic episodes, have been observed in insulin-naïve patients with T2DM titrating Gla-100 using a TTT algorithm. Of these studies, only a handful have been conducted specifically in Asian populations [18, 28]. Thus, there is a lack of information and guidance on the appropriate frequency of titration, safe dose increments, and the maximal dose of basal insulin for Asian populations. Studies need to be conducted to enable an adequate understanding of the pathophysiology of Asian patients and therefore how insulin requirements, treatment goals, and the risk of hypoglycemia differ from those for Caucasian patients.

In order to provide some guidance, based on their own clinical experience, the authors recommend that with careful monitoring, the presence of hypoglycemia may be taken as an indication that the basal insulin dose is too high. Consideration should be given to any dose adjustments to OADs that might be required with basal insulin initiation and titration. The authors recommend, despite current real-world practices in Asia, that the optimal time for initiation of basal insulin should follow approximately 3 months of failure of metformin monotherapy and lifestyle modifications, as summarized in Fig. 1. The recommended titration algorithm given in Table 3 involves a low dose of basal insulin for initiation to avoid hypoglycemia, and subsequent dose adjustments based on predefined physiologic targets. When choosing this algorithm, it is important that other patient- and disease-specific factors are also taken into consideration.

The management of insulin therapy is a multidisciplinary team effort that involves specialists, primary care physicians, nurse educators, and patients. Due to the high prevalence of T2DM in Asia [5], it is vital that primary care providers, patients, and other HCPs are able to adequately manage insulin therapy; to achieve this, greater education and resources on the optimal titration of basal insulin need to be targeted at these groups.

The time and resource constraints that primary care physicians face [34, 37, 38] could potentially be relieved through the use of modern technology, including web-based tools, mobile applications, cell-phone-based support, glucometers capable of uploading data to the web, and telephone hotlines [40‐42, 44, 45, 48, 49, 73]. As an example, one of the authors of this paper has implemented the titration of insulin through the medium of SMS in his clinical practice in Indonesia. Patients send their SMBG readings by SMS every 3–7 days to their clinician (author) and receive advice via a return SMS regarding changes in their insulin dose. The author has reported that patients are satisfied with this method of communication because of its efficiency and the amount of attention from the physician that it affords. In another author’s clinical practice in the Philippines, patients relay their SMBG readings through SMS or by phone call and accordingly receive advice on their readings through phone calls. Patients have reported satisfaction with this method as it saves on travel time to the clinic and circumvents the need to take time off work to attend clinic appointments.

With regard to technology-based methods, care should be taken to implement these in the right settings. Other approaches to titration, for example group titration and education, may be effective for elderly patients who may not be comfortable with the use of technology. Titrating and providing education in groups not only reduces the amount of time needed with each patient but also creates an environment that allows patients to discuss and share their problems as well as support each other [26].

To reduce the burden on primary care physicians, diabetes nurse educators should be empowered to provide patients with guidance on titration. Nurse-led care is a practical and cost-effective model, and is effective in maintaining optimal glycemic control of patients as well as enhancing their adherence to treatment [74]. One example of facilitating nurse-led care could be to set up nurse-led titration clinics. Technology could also be taken advantage of to support nurse-led titration. A study has demonstrated that patients can effectively titrate their doses of Gla-100 and improve their glycemic control through SMS/phone call contact with their diabetes nurse educators. This method also reduced travel time, time spent in the waiting room, and the overall cost of treatment for patients [42].

Despite an increasing drive for patients to be more involved in the management of their disease [9, 75, 76], physicians often are of the opinion that patients are unable or unprepared to effectively self-titrate and manage their insulin dose. The ATLAS study has demonstrated that patients in Asia are able to effectively titrate their dose of Gla-100 when provided with guidance [18]; however, only a few clinical studies investigating the self-titration of basal insulin amongst patients with T2DM have been conducted [18, 39]. To increase awareness of self-titration, as well as provide specialists and primary care physicians with evidence that patients are able to effectively self-titrate their insulin, further studies investigating patient-led titration specifically in Asian populations should be conducted. Supporting patients is also vital, and can be achieved through various measures, such as by setting up insulin titration clinics as well as enrolling patients into patient support programs that encourage self-titration. Mobile and web-based technologies can also empower patients with the confidence to self-manage their disease to a greater extent, and various studies have demonstrated that by using these technologies, patients are able to effectively titrate their basal insulin for improved glycemic control. Patients are often frustrated with the time it takes to attain adequate glycemic control [77], and involving them in their own treatment can potentially help to resolve this.

The ultimate goal of the research and recommendations outlined in this article is to enable patients with T2DM to achieve optimal glycemic control. The authors acknowledge that achieving this requires patients to control their postprandial BG in addition to their FPG, possibly requiring a prandial insulin. Dose optimization of basal and prandial insulin analogs together is therefore a subject for future consideration.

We have reviewed the efficacy and safety of titrating Gla-100, and highlighted the importance of optimal dose titration in supporting Asian patients with T2DM to achieve glycemic control. Specific challenges exist within Asia that impact basal insulin titration and therefore affect treatment outcomes. These include the strong ethnic association with and genetic predisposition to diabetes among Asians [4, 78], as well as the relatively long delays incurred before insulin initiation and suboptimal dose titration, which have been reported in several countries [11, 18‐21]. Current treatment guidelines recommend early initiation of basal insulin therapy, and subsequent effective patient- or physician-led dose titration regimens to facilitate dose optimization [9, 63, 65‐67, 69, 71]. In the past decade, various studies have illustrated that titration of Gla-100 using the TTT method has been able to aid patients in achieving HbA_1c < 7% [32, 33], and early intervention with basal insulin has been shown to maintain glycemic control in the long term [10]. Early initiation and optimal titration of basal insulin is therefore key to improving patient outcomes. Given the success with patient-led dose titration observed in several studies [16, 18, 39], this method could prove to be an effective means of optimizing treatment. Thus, future initiatives in Asia should embrace educational support to promote patient-led approaches so as to empower individuals with T2DM to take control of their treatment [18]. Additionally, the use of mobile and web-based technologies has the potential to facilitate successful collaboration between patients and HCPs [40‐44] and therefore improve the titration of basal insulin and the management of diabetes as a whole, and should be further used and encouraged.