Use of Second-Generation Basal Insulin Gla-300 in Special Populations: A Narrative Mini-Review

Background and Aims Hypoglycemia and insulin-related adverse events are crucial barriers to effective diabetes management, particularly in the elderly, people with renal impairment, people with diabetes fasting during Ramadan, or people with type 1 diabetes mellitus (T1DM). There is a scarcity of clinical and real-world evidence assessing the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) in these special populations. To understand the entirety of evidence, this mini-review elaborates on the use of Gla-300 in diabetes management among special populations. Methods Clinical and real-world evidence related to the use of Gla-300 among special populations with diabetes were retrieved using PUBMED and Google Scholar. Results Gla-300 has shown improved glycemic control with stable insulin action and low risk of hypoglycemia in diverse groups with diabetes. It also appears to have an acceptable safety profile during Ramadan fasting. However, adequate monitoring and adjustment of insulin dose on an individual basis should be considered. Conclusion Gla-300 is a second-generation basal insulin with proven benefits of reduced risk of hypoglycemia and improved glycemic control in special populations of people with diabetes.


INTRODUCTION
Basal insulin (BI) therapy is a widely used option among available insulin therapies and requires a balance between achieving individualized glycemic targets and reducing hypoglycemia.Multiple risk factors attributable to the increased risk of hypoglycemia are older age, renal impairment, long duration of diabetes, history of severe hyperglycemia, and the presence of comorbidities [1][2][3][4][5][6].However, an increased risk of hypoglycemia and associated fear of firstgeneration BIs are the obstructing factors in their continued use among these vulnerable populations.Second-generation BI analogues, insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg), have been increasingly used for diabetes management among clinicians as they provide a wide range of advantages including longer duration and stable insulin action, and comparable glycemic efficacy with lower hypoglycemia risk compared to the first-generation BI analogues [7][8][9][10].Growing evidence suggests that these second-*Address correspondence to this author at the Department of Endocrinology, Bharti Hospital, Kunjpura Road, Model Town, Sector 12, Karnal, Haryana 132001, India; Tel: +91-9896048555; E-mail: brideknl@gmail.comgeneration BI analogues have potential benefits if used in special populations with diabetes at high risk of hypoglycemia.This mini-review describes the role of Gla-300 in achieving improved glycemic control and low risk of hypoglycemia among special populations with diabetes, including older people, people with renal impairment, type 1 diabetes mellitus (T1DM), and people fasting during Ramadan.

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Clinical and real-world evidence related to the use of Gla-300 among special populations with diabetes (including older age groups, people with renal impairment, people with T1DM, and people fasting during Ramadan) and published up to 06 October 2021 were searched using PUBMED and Google Scholar.The following search terms were used in combination with appropriate MeSH terms: Chronic kidney disease, CKD, elderly, insulin, Glargine, U-300, Gla-300, hypoalbuminemia, Ramadan, renal impairment, type 1 diabetes mellitus, T1DM, type 2 diabetes, and T2DM.A manual search was further performed through internet and the references of the identified articles were scanned to find the studies that were not retrieved through the electronic database search; these included published congress abstracts as well.

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Hypoglycemia incidence over the 24 weeks was similar.
ATOS study-subgroup analysis [25] Insulin naïve people with T2DM along with (n=581) or without (n=3841) a history of renal impairment

Gla-300
In people with renal impairment vs. without renal impairment:

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Gla-300 provided a benefit of achieving glycemic control without hypoglycemia over Gla-100.

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No unprecedented adverse events observed during 1-year of study period indicate safety of Gla-300.

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Overall low incidence of severe and/or symptomatic hypoglycemia (2.6%), with no severe hypoglycemic events reported during Ramadan.

Renal Impairment
Renal impairment is an independent risk factor for hypoglycemia which increases the risk of hypoglycemia in people with type 2 diabetes mellitus (T2DM) [11,12].A strong evidence base indicates that diabetes management in this population is complex and increased hypoglycemia risk associated with cardiovascular morbidity and mortality, ultimately limits the options for glucose-lowering therapy [13][14][15][16].Owing to the high risk of hypoglycemia and reduced renal clearance in people with T2DM and chronic kidney disease (CKD), an insulin treatment that decreases glycated hemoglobin (HbA1c) without escalating the risk of hypoglycemia is clinically important.Subgroup analyses according to renal function categorization from various randomized controlled trials (RCTs) and real-world studies have provided promising results with Gla-300 use.A meta-analysis of pooled 6month data from EDITION 1, 2, and 3 trials according to renal function subgroups shows comparable glycemic control (decrease in HbA1c and the proportion of people achieving HbA1c targets) with Gla-300 vs. glargine 100 U/mL (Gla-100) at once-daily dosage in T2DM cohort.Furthermore, Gla-300 offered a lower risk of nocturnal confirmed or severe hypoglycemia (vs.Gla-100), irrespective of renal function subgroups.These findings indicate the benefit of reduced risk of hypoglycemia with Gla-300 in individuals with T2DM and impaired renal function [17].In addition, the BRIGHT study, which compared two second-generation BIs (Gla-300 vs. IDeg-100) head-to-head, has provided important information about the effectiveness and safety of Gla-300 in insulin-naïve individuals with T2DM and renal impairment.The heterogeneity of treatment effect across renal function subgroups (P=0.02) and greater reduction in HbA1c with Gla-300 vs. IDeg-100 among those with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m 2 (mean difference: -0.43% (95% CI: -0.74%, -0.12%)) were observed.Hypoglycemia incidence over the 24 weeks was similar across both the treatment arms; thus, suggesting better effectiveness of Gla-300 over IDeg-100 without compromising safety [18].A recent report from REALI CKD pooled analysis also demonstrated concordant observations in terms of the clinically significant glycemic control with favorable hypoglycemia risk in a diverse group of renal function subgroups (baseline eGFR: ≥90, 60-89, 45-59, and 15-44 mL/min/1.73m 2 ) indicating no influence of baseline renal function on the effectiveness and safety of Gla-300 during six months of treatment in individuals with poorly controlled T2DM [19].Further additional studies in individuals with more advanced renal impairment (eGFR <45 or <30 mL/min/1.73m 2 ) would be useful.Coming to the realworld evidence, currently, four studies are available that provide corroborating observations to the above-mentioned trials.In DELIVER D+ study, analysis of people with moderate-to-severe renal impairment demonstrated the effectiveness of Gla-300 in achieving improved glycemic control and lower hypoglycemia incidence after switching from a firstgeneration BI analogue (Gla-100/detemir) [20].On the contrary, observations from DELIVER High Risk study showed that switching to Gla-300 resulted in significantly lower risk of hypoglycemia (P=0.006) and emergency department/hospitalization related to hypoglycemia (P=0.022) in people with moderate-to-severe renal impairment [21].The LIGHTNING study demonstrated significantly lower predicted rates of severe hypoglycemia with Gla-300 use (vs.first-generation BI) [22].In accordance with the previously discussed evidence, the ACHIEVE Control study also showcased the potential benefit of Gla-300 (vs.standard-of-care BI analogue) in terms of hypoglycemia avoidance in those with renal impairment; particularly in those with moderateto-severe renal impairment for a 1-year treatment duration (odds ratio >1.40) [23].Another real-world study, ATOS (NCT03703869), was conducted prospectively across multiple countries (n = 388) for a period of one-year (n = 4589 participants) to assess the clinical effectiveness, safety and health-economic benefits of Gla-300 initiation in insulinnaïve people with T2DM who failed to achieve glycemic control with OADs [24].A subgroup analysis of ATOS study also indicated the effectiveness of Gla-300 in improving glycemic control and reducing hypoglycemia risk independent of an individual's renal impairment history [25].In summary, the aforementioned real-world studies provide complementary findings that support results from RCTs and reflect the effectiveness and safety of Gla-300 from routine clinical practice in people with T2DM and renal impairment.

Hypoalbuminemia
The only study evaluating the differential effect of hypoalbuminemia on hypoglycemia in 30 individuals with T2DM treated with Gla-300 and IDeg reported that in those with serum-albumin levels <3.8 g/dL, the mean percentages of time with hypoglycemia (1.9 vs. 11.1;P=0.002), clinically important hypoglycemia (0.02 vs. 3.64, P=0.002), and nocturnal hypoglycemia (1.5 vs. 7.4; P=0.004) were lower in Gla-300 vs. IDeg group [26].Therefore, it may be necessary to consider the risk of nocturnal hypoglycemia based on albumin levels when using IDeg; however, the use of Gla-300 may be unaffected by albumin levels.This is an interesting finding showing a signal of benefit for Gla-300 use.It should be noted that this study had a small sample size (n = 30); therefore, more evidence and large-scale studies are needed to corroborate these findings.

Older Population
Older people with diabetes are more prone to hypoglycemia and impaired awareness of hypoglycemia than younger populations [27,28].Older individuals with the incidence of hypoglycemia during the initial phase of BI treatment are at high risk of hospitalization or death [29].Therefore, minimizing the hypoglycemia risk is vital and several clinical and real-world studies have evaluated efficacy/effectiveness and safety of Gla-300 in older people with diabetes.
The SENIOR trial demonstrated that the Gla-300 was effective in older people (≥65 years) with lower rates of documented symptomatic hypoglycemia at any time of day (24 hours) vs. Gla-100, particularly in those aged ≥75 years (rate ratio 0.45 [95% CI, 0.25, 0.83]) [30].In the pooled analysis of EDITION trials, at the end of six months, compared to Gla-100, Gla-300 demonstrated a reduced risk of nocturnal confirmed or severe hypoglycemia and documented symptomatic hypoglycemia along with a comparable glycemic control in older (≥65 years) population with T2DM.Additionally, Gla-300 provided the benefit of achieving glycemic control without hypoglycemia over Gla-100 [31].
Furthermore, a pooled analysis of EDITION 2 and 3 trials reported an additional benefit of less weight gain associated with Gla-300 vs. Gla-100 among older (>55 years) people with T2DM [32].On the contrary, BRIGHT Elderly study (post hoc analysis of BRIGHT) reported apparently greater HbA1c reduction and similar hypoglycemia risk with Gla-300 vs. IDeg in older adults (≥70 years).In the initial 12-week titration period, Gla-300 group showed consistently lower incidence and rates of anytime and nocturnal severe or confirmed hypoglycemia compared with IDeg group irrespective of age subgroups (</≥65 years and </≥70 years) [33,34].
Real-world evidence from DELIVER 3 study involving older individuals (≥65 years) with T2DM mirrored observations from clinical trials.Switching to Gla-300 vs. firstgeneration BIs was associated with greater/similar improvements in glycemic control and Gla-300 significantly reduced the risk of hypoglycemia in this population [35].Similarly, the observations of the REALI pooled analysis indicate the potential use of Gla-300 in older people prone to hypoglycemia.The incidences of symptomatic hypoglycemia during any time of the day (5.9% vs. 7.6%-9.4% for the younger subgroups) or night-time (0.5% vs. 1.6%-2.5%)were lower in those aged ≥80 years compared to younger age subgroups (subgroups:<50, 50-59, 60-69, 70-79 years) [36].With simi-lar hypoglycemia risk, evidence from X-STAR study reassures safety of Gla-300 in T2DM cohort of older age or with renal impairment [37].A subgroup analysis of ATOS study indicated that Gla-300 was beneficial in attaining target HbA1c and reduced risk of hypoglycemia among people with T2DM irrespective of their age groups [38].
To summarize, all of these studies show that Gla-300 has a low risk of hypoglycemia across a wide age range (>55 to 80 years) while maintaining glycemic control.

People with T1DM
Extensive literature search has identified multiple studies evaluating pharmacokinetic-pharmacodynamic (PK-PD) profile of Gla-300 in comparison to other BIs in people with T1DM.These data demonstrate less glycemic variability and stable glucose profile when administered at any time of the day indicating possible flexibility of dosing [7,8,39,40].Furthermore, the individualized, clinical doses of Gla-300 and Gla-100 resulted in a similar euglycemic potential under steady state conditions; however, Gla-300 administered in the evening exhibited a more stable profile, with lower variability and more physiological modulation of hepatic glucose production compared with Gla-100 [41].Therefore, Gla-300 (if administered in the evening) can be advantageous in terms of lowering the risk of nocturnal hypoglycemia, improving predinner hyperglycemia, and reducing within-day glucose variability in those with T1DM.Gla-300 showed 20% lesser within-day glycemic variability when compared with IDeg-100 in a euglycemic clamp study in individuals with T1DM [39].On the contrary, Heise et al. showed significantly lower relative within-day and day-to-day variability with IDeg compared to Gla-300 [42].However, yet another study conducted by Lucidi et al. demonstrated that Gla-300 had lower within-day variability compared to IDeg-100 despite even distribution of insulin activity over 24 h post-dosing [40].
Comparison of Gla-300 with Gla-100 in EDITION 4 trial reported comparable HbA1c reduction with similar incidence of overall hypoglycemia.However, Gla-300 showed reduced nocturnal hypoglycemia incidence during the initial titration period in T1DM [43].Furthermore, several other RCTs have established supporting evidence for Gla-300 use over other BIs in terms of lower risk of nocturnal or severe hypoglycemia [44][45][46].A pooled analysis of EDITION 4, EDITION JP1, and EDITION JUNIOR trials also revealed lower risk of severe hypoglycemia with Gla-300 vs. Gla-100 [43].Switching to Gla-300 once-daily from other BI (twice-daily) analogues improved glycemic control and treatment satisfaction among people with T1DM [47,48].These observations are replicated in real-world clinical practice as well [49,50].
Further, the real-world evidence from across the world supports the above-discussed benefits of Gla-300 in T1DM management along with the highest persistence rate [50][51][52].In particular, Gla-300 has been shown to be effective in substantial improvement in HbA1c reduction with reduced incidence of nocturnal or severe hypoglycemia episodes and diabetic ketoacidosis [53,54].The REALITY study from Canada demonstrated that those with T1DM switching to Gla-300 had significant reductions in HbA1c with no change in weight or insulin dose [55].Similarly, the recent RE-STORE-1 study showed that switching from first-generation BI to Gla-300/IDeg was associated with similar improvements in glycemic control and overall significant decrease in hypoglycemia, with no severe events in Gla-300 group vs. seven events in IDeg group (P=0.02)[56].
Further, the OneCARE real-world study has demonstrated a comparable safety and effectiveness profile of Gla-300 and IDeg in terms of achieving a full day time in range (TIR) 70-180 mg/dL; however, those receiving Gla-300 spent significantly higher time in target glucose range (TIR 70-140 and 70-180 mg/dL) and lower time above range (>180 mg/dL) at night-time than IDeg, indicating the lower risk of nocturnal hypoglycemia with Gla-300 use [57].
A post-marketing surveillance data from Japanese X-STAR study highlights the safety of Gla-300 with no unprecedented adverse events observed during 1-year of study period.Due to blunted up-titration (+1.13 U/day [+0.02 U/kg/day]) of the Gla-300 dose, the HbA1c reduction over 12 months (-0.12%) was slightly moderate in this real-world study compared with the clinical trial data [58][59][60].Therefore, for better glycemic control, clinicians should apply vigilant up-titration of Gla-300 with a careful consideration for hypoglycemia risk in a real-world setting.To summarize, the overall evidence suggests the potential benefit of Gla-300 among the T1DM population in terms of lower risk of nocturnal or severe hypoglycemia, improved glycemic control, and better treatment satisfaction compared to first-generation BIs.

Ramadan
Management of diabetes during Ramadan fast is a crucial challenge for insulin users as long hours of fasting can make them more susceptible to potential complications (severe hypoglycemia, hyperglycemia, and ketoacidosis).Realworld evidence from ORION study showed overall low incidence of severe and/or symptomatic hypoglycemia, with no severe hypoglycemic events reported during Ramadan and clinically improved glycemic control from pre-Ramadan to post-Ramadan period [61].Therefore, Gla-300 seems to be a promising insulin therapy for diabetes management in people fasting during the Ramadan period.

CONCLUSION
Gla-300 is a second-generation BI with proven benefits of reduced risk of hypoglycemia and improved glycemic control in special population of people with diabetes, including those with renal impairment, older individuals, and T1DM.It also appears to have an acceptable safety profile during Ramadan fasting.However, while using Gla-300 in these special populations, adequate monitoring and adjustment of insulin dose on an individual basis should be considered.Future clinical and real-world studies exploring use of Gla-300 will provide more information on its effectiveness and safety.

DISCLOSURES
All authors had full access to the articles reviewed in this manuscript, have read and reviewed the final draft of this manuscript and take complete responsibility for the integrity and accuracy of this manuscript.The content published herein solely represents the views and opinions of the authors.The details published herein are intended for informational, educational, academic and/or research purposes and are not intended to substitute for professional medical advice, diagnosis or treatment.

CONSENT FOR PUBLICATION
Not applicable.

FUNDING
Medical writing and journal open access fees for this article were paid by Sanofi, India.The authors did not receive any fee/payment/honoraria from Sanofi directly or indirectly related to the development of this article.

CONFLICT OF INTEREST
SG and GB have no potential conflict of interest to declare.RKS is an Advisory Board Member for Boehringer Ingelheim, Dr. Reddy's Laboratories, Eli Lilly, and Sanofi and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi.SK received honoraria/speaker fees from Eli Lilly, Novo Nordisk, and Sanofi.

Table 1) Contd… Study Details Study Cohort (Sample Size) Treatment Summary of Key Observations Hypoalbuminemia
(