Clinical perspectives on the frequency of hypoglycemia in treat-to-target randomized controlled trials comparing basal insulin analogs in type 2 diabetes: a narrative review

Abstract

Introduction

As recommended by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) 2022 consensus on the management of hyperglycemia,¹ basal insulin has been replaced by injectable incretin-related therapy as the first-line injectable therapy for type 2 diabetes (T2D) insufficiently controlled by combinations of oral glucose-lowering agents. However, many individuals with T2D may still eventually require basal insulin as beta-cell function declines over time or if insufficiently controlled by injectable incretin-related therapy.²

Hypoglycemia is a common adverse event associated with insulin therapy, and hypoglycemia risk increases with intensive glycemic control and duration of T2D.³ Optimizing T2D management with insulin therapy is therefore a balancing act between achieving optimal glycemic control while minimising hypoglycemia risk, irrespective of the insulin formulation used in clinical practice. Overall hypoglycemia may be considered as any episode with blood glucose (BG) <3.9 mmol/L (<70 mg/dL) irrespective of time of day. ‘Level 1’ hypoglycemia consists of BG values between 3.0 and 3.9 mmol/L (54–70 mg/dL), which are regarded as ‘alerts’ to take action but do not have regulatory implications.^{4 5} Clinicians and regulators consider ‘level 2’ (or ‘clinically significant’) hypoglycemia, defined as a BG value <3.0 mmol/L (<54 mg/dL), and ‘level 3’ (or ‘severe’) hypoglycemia, defined as an episode causing sufficient cognitive impairment to require assistance from another person, to be most relevant when evaluating treatment.^{4 6} Both level 2 and level 3 hypoglycemia have substantial clinical impacts, increasing mortality and morbidity^{7 8} while also reducing quality of life⁹ and exerting indirect effects via increased healthcare resource utilization (ie, hospital admissions), increased workplace absenteeism and reduced productivity.¹⁰ Recent real-world analyses in the USA show alarmingly high rates of level 3 or severe hypoglycemia, supporting the urgent need for hypoglycemia-mitigating interventions.¹¹

Over the past three decades, there have been major improvements in the pharmacokinetic (PK) and pharmacodynamic (PD) properties of basal insulins, starting with first-generation basal insulin analogs (ie, insulin detemir (detemir) and insulin glargine U100 (glargine U100)), generating more predictable, longer-acting soluble formulations with flatter PK and PD profiles among insulin analogs, resulting in reduced hypoglycemia risk compared with neutral protamine Hagedorn (NPH) insulin.^12–14

The ‘Treat-To-Target’ Study published in 2003, comparing glargine U100 with NPH insulin, led to a paradigm shift in the accepted standard of care regarding insulin therapy for T2D.¹⁵ This trial established the concept of gradually increasing the insulin dose to attain a predefined fasting glucose target or until unacceptable hypoglycemia occurs. This ‘treat-to-target’ approach would thus enable glycated hemoglobin (HbA1c) parity between comparators, and in turn allow for differentiation based on other outcomes of interest (eg, hypoglycemia). This study reduced hypoglycemia risk using basal insulin analogs that showed a more predictable PK/PD; this enabled systematic insulin titrations resulting in fewer hypoglycemic episodes, particularly at night.¹⁶ Subsequent development of second-generation insulin analogs with an even longer duration of action, flatter insulin PK/PD profiles, and lower insulin peak:trough ratios (ie, more constant circulating insulin levels), such as insulin degludec (degludec) U100 and U200, and insulin glargine U300 (glargine U300), further reduced hypoglycemia risk compared with glargine U100.^17–19

Despite these developments, hypoglycemia remains a fundamental challenge of basal insulin therapy. Fear of hypoglycemia, delays in treatment initiation partly due to the injection barrier, titration inertia and a lack of concordance are perhaps the main barriers to the effective use of insulin therapy in patients with T2D.^{20 21} To help overcome clinical inertia and to reduce the injection burden with daily basal insulin, two once-weekly basal insulins have been developed and are in late-stage clinical trials: insulin icodec (icodec) and basal insulin Fc efsitora alfa (efsitora). The efficacy of icodec and efsitora was demonstrated in phase 1 and phase 2 randomized clinical trials (RCTs),^22–28 and further confirmed for icodec in the phase 3a ONWARDS program in insulin-naive individuals newly initiating insulin, individuals treated with basal insulin alone or individuals already established on basal-bolus insulin regimens.^29–34

Given the protracted duration of action of once-weekly insulin, physicians may have a theoretical concern regarding the risk of hypoglycemia.³⁵ Contextualizing the risk of hypoglycemia observed with once-weekly insulin in RCTs requires a clear and up-to-date understanding of the risk of hypoglycemia seen with currently available once-daily or two times per day basal analogs. However, owing to heterogeneity in trial designs, hypoglycemia definitions, titration interventions and study populations, it is difficult to compare hypoglycemia outcomes between RCTs in a formal meta-analysis. Therefore, the aim of this narrative review was twofold: (1) to define the hypoglycemia risk with current one or two times per day basal insulin analogs; and (2) to use these data to help contextualize emerging once-weekly basal insulin hypoglycemia data. Here, we comprehensively summarize mean hypoglycemia rates from treat-to-target trials of daily basal insulins in T2D conducted over the past 22 years (2000–2022), with reference to the differences between studies. Importantly, given the narrative nature of this review, no comparative statistical analyses were possible.

Methods: trial identification and data extraction

Published articles were identified in Ovid MEDLINE and Embase via targeted searches using the search strings shown in online supplemental table 1. The US Food and Drug Administration (FDA) submission documents for glargine U100,³⁶ detemir,³⁷ degludec³⁸ and glargine U300³⁹ were also used to source additional studies. Only English articles were included.

Treat-to-target RCTs (sample size >30 participants/arm) assessing daily basal insulins (detemir, glargine U100, degludec and glargine U300) in adults (≥18 years of age) with T2D conducted between January 1, 2000 and December 30, 2022 and reporting BG-confirmed hypoglycemia were eligible for inclusion. RCTs assessing premix insulin or fixed-dose basal insulin/glucagon-like peptide-1 receptor agonist (GLP-1 RA) combinations without a basal-only insulin arm were not eligible. Data from phase 3a RCTs assessing icodec were added during development, as the publications became available.^{30–33 40}

The primary outcomes of interest were the mean event rates/person-year of clinically relevant ‘level 2’ hypoglycemia (BG value <3.1 mmol/L (55 mg/dL) or <3.0 mmol/L (54 mg/dL)), severe ‘level 3’ hypoglycemia, overall hypoglycemia (any BG value <3.9 mmol/L (70 mg/dL) irrespective of time of day) and nocturnal hypoglycemia; these definitions were selected to provide the greatest data inclusivity, given the changes in hypoglycemia definitions over time. Prior to 2017 and the position statement by the International Hypoglycaemia Study Group,⁵ the glucose threshold for ‘level 2’ hypoglycemia was applied arbitrarily across studies; hence, both <3.1 mmol/L (55 mg/dL) and <3.0 mmol/L (54 mg/dL) thresholds have been accounted for in the analysis. Hypoglycemia rates are presented as events/person-year of exposure (PYE) reported for the defined study treatment period. Continuous glucose monitoring (CGM)-based time below range (TBR), defined as proportion of time spent with sensor glucose levels below target range (<3.9 mmol/L (<70 mg/dL)), was also captured; however, trials reporting CGM-based hypoglycemia without also providing BG-confirmed values were excluded. Study design and participant baseline characteristics (body mass index (BMI), HbA1c, age and diabetes duration), in addition to changes in HbA1c from baseline to end of treatment (EOT), were also captured. Sulfonylurea usage and continuation (yes/no) after trial randomization was also extracted. As access to the raw data was not possible, and to avoid any inadvertent introduction of errors, all data reported here employ the format and number of decimal places used in the original publication.

Overview of treat-to-target daily basal insulin trials in people with T2D (2000–2022)

Impact of study factors on overall hypoglycemia rates

To investigate the impact of hypoglycemia definition, overall hypoglycemia rates were grouped by respective study into two categories: (1) overall severe or BG-confirmed <3.9 mmol/L (<70 mg/dL) and (2) overall severe or BG-confirmed <3.1 mmol/L (<55 mg/dL) or <3.0 mmol/L (<54 mg/dL) (figure 1A,B). Hypoglycemia event rates were variable, with broader rate ranges observed among trials using a threshold of <3.9 mmol/L (<70 mg/dL; figure 1A)^{45 54 56 58 61 64–66} than among those with BG <3.1 mmol/L (<55 mg/dL)^{46–53 55 57 59 60 63 67–69} or <3.0 mmol/L (<54 mg/dL^{17 24 45}; figure 1B). Hypoglycemia rates were generally higher for basal-bolus trials^{60 61 63} than for basal-only trials in both insulin-naive^{32–34 41 45 46 48–52 54–58 64 67 68 70–84} and insulin-experienced individuals,^{47 53 65 66 69 79 85} whereas rates for mixed population trials tended to be in the middle (figure 1A,B). For overall severe or BG-confirmed <3.9 mmol/L (<70 mg/dL), hypoglycemia rates ranged from 0.7 to 8.5 events/PYE for basal-only (insulin-naive) trials (glargine U100, 0.7–8.5; glargine U300, 1.4–6.4),^{45 54 56 58 64} from 3.36 to 18.14 events/PYE for basal-only (insulin-experienced) trials (glargine U100, 3.36–18.14; degludec, 4.22–3.39; glargine U300, 6.76–14.01),^{65 66} and from 11.24 to 26.76 events/PYE for the basal-bolus trial⁶¹ (glargine U100, 11.24–26.76; glargine U300, 11.39–25.48; figure 1A). For overall severe or BG-confirmed <3.1 mmol/L (<55 mg/dL) or <3.0 mmol/L (<54 mg/dL), hypoglycemia rate ranges (events/PYE) were 0.06–7.14 for basal-only (insulin-naive) trials (NPH insulin 7.14; detemir 0.23–3.67; glargine U100, 0.06–2.9; glargine U300, 0.11–0.24; degludec, 0.09–1.6),^{46 48–52 55 57 67 68 77 80 83 84} 0.28–5.66 for basal-only (insulin-experienced) trials (glargine U100, 0.28–2.75; glargine U300, 1.11–1.64; degludec, 0.28–5.66),^{47 53 69 79 85} and 2.43–13.63 for basal-bolus trials (glargine U100, 2.56–13.63; glargine U300, 2.43–3.78; degludec, 11.09)^{60 63} (figure 1B).

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Figure 1

Overall hypoglycemia rates grouped according to hypoglycemia definitions (blood glucose thresholds: ≤3.9 mmol/L [≤70 mg/dL] [Panel A], <3.1 mmol/L [<55 mg/dL] or <3.0 mmol/L [<54 mg/dL] [Panel B]) used for treat-to-target basal-only (BO) and basal-bolus insulin T2D trials. Hypoglycemia rates are shown as events/PYE. Each data point represents a single trial. Six BO (insulin-naive) trials reported data for multiple basal insulins (Bolli et al ⁴⁵; Hermansen et al ⁵⁰; Meneghini et al ¹⁰¹; Pan et al ⁴⁶; Rosenstock et al ⁵⁷; Zinman et al ⁶⁷); two BO (insulin-experienced) trials reported data for multiple basal insulins (Yki-Järvinen et al ⁶⁵ and Wysham et al ⁸⁵). BG, blood glucose; degludec, insulin degludec; detemir, insulin detemir; glargine U100, insulin glargine U100; glargine U300, insulin glargine U300; NPH, neutral protamine Hagedorn insulin; PYE, person-year of exposure; T2D, type 2 diabetes.

Overall severe or BG-confirmed hypoglycemia rates <3.1 mmol/L (<55 mg/dL) or <3.0 mmol/L (<54 mg/dL) were grouped according to concomitant sulfonylurea usage (figure 2A), EOT basal insulin dose (figure 2B) and change from baseline to EOT in HbA1c (figure 2C). No trends were observed across these parameters. Similarly, achieving EOT HbA1c <7.0% vs ≥7.0% did not consistently lead to higher severe or BG-confirmed hypoglycemia rates (online supplemental figure 1).

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Figure 2

Overall hypoglycemia rates (overall severe or BG-confirmed/BG-confirmed value of <3.0 mmol/L (<54 mg/dL) or <3.1 mmol/L (<55 mg/dL)) grouped according to sulfonylurea usage (A), EOT basal insulin dose (B) and change from baseline to EOT in HbA1c (C). Hypoglycemia rates are shown as events/PYE. Each data point represents a single trial; some trials reported hypoglycemia rates for more than one basal insulin. Numbers of data points differ across panels because not all trials reported sulfonylurea usage or the insulin dose used. BG, blood glucose; BO, basal-only; degludec, insulin degludec; detemir, insulin detemir; EOT, end of treatment; glargine U100, insulin glargine U100; glargine U300, insulin glargine U300; HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; PYE, person-year of exposure.

Exploring trends in hypoglycemia rates across different study populations

CGM-measured hypoglycemia: TBR

CGM-measured TBR data were only reported for two glargine U100 basal-only trials (figure 3)^{71 86}: a head-to head trial of glargine U100 versus degludec in insulin-experienced individuals,⁸⁶ and a glargine plus sulfonylurea (gliclazide) evaluation in insulin-naïve individuals.⁷¹ Blinded CGM was used in both trials.

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Figure 3

CGM-measured TBR (over a 24-hour period) for glargine U100 basal-only trials in insulin-naive individuals with T2D. Observed data are reported for Bajaj et al.⁷¹ Estimated data are reported for Goldenberg et al.⁸⁶ In Bajaj et al, individuals wore blinded CGM devices during week 13. In Goldenberg et al (a 41-week crossover trial of glargine U100 vs degludec), after a 2-week screening period (week −4 to week −2) and a 2-week run-in period (week −2 to week 0), there were two consecutive 16-week treatment periods (weeks 0–16 and weeks 18–34), each followed by a 2-week maintenance period (weeks 16–18 and weeks 34–36); at the end of the second treatment period, there was a 1-week follow-up (weeks 36–37). The data shown in the figure are that collected during the two 2-week maintenance periods and were recorded by participants using a blinded CGM device. CGM, continuous glucose monitoring; degludec, insulin degludec; EOT, end of treatment; glargine U100, insulin glargine U100; GLC, gliclazide; HbA1c, glycated hemoglobin; T2D, type 2 diabetes; TBR, time below range; U, units.

In the head-to-head trial,⁸⁶ the proportion of TBR was numerically lower with degludec than with glargine U100, despite an identical titration target of 3.9–5.0 mmol/L (70–90 mg/dL); both degludec and glargine U100 demonstrated similar HbA1c reductions from baseline (−0.5% vs −0.4% points, respectively; baseline: 7.6%) and comparable EOT insulin doses (56 vs 59 U/day). Overall, for glargine U100 and degludec, the proportion of TBR for level 1 hypoglycemia (sensor glucose 3.0–3.8 mmol/L (54–68 mg/dL); recommended target <4.0%) was 6.3% and 5.8%, while for level 2 hypoglycemia (sensor glucose <3.0 mmol/L (<54 mg/dL); recommended target <1.0%), it was 2.5% and 2.2%, respectively. The estimated mean treatment difference (degludec−glargine U100) in TBR for level 2 hypoglycemia was −0.24 (95% CI −0.79 to 0.31), which was not statistically significantly different.⁸⁶

Overall hypoglycemia rates with once-weekly insulin

The efficacy and safety of once-weekly insulin in T2D were investigated in three phase 2 icodec studies,^{22 23} five phase 3 icodec studies (ONWARDS 1–5)^{29–33 40} and two phase 2 efsitora alfa studies.^{27 28} In the icodec phase 3a studies, sulfonylureas were either discontinued or reduced by 50% at the investigator’s discretion to mirror real-world conditions.^{29–33 40} In ONWARDS 1 and ONWARDS 3, overall level 2 and 3 hypoglycemia rates (events/PYE) in basal-only insulin-naive individuals ranged from 0.19 to 0.31 for icodec, compared with 0.16 for glargine U100 and 0.15 for degludec (figures 1B and 2), with overall HbA1c reductions ranging from −1.3% to −1.6% points (baseline range: 8.4–8.6%), confirming statistical non-inferiority and superiority of icodec versus respective once-daily comparators.^{32 33} In insulin-naive individuals, icodec plus a dosing guidance app was also compared against a pooled group of once-daily basal insulin analogs (degludec, glargine U100 or glargine U300) administered following real-world practice; overall combined level 2 or level 3 hypoglycemia rates (events/PYE) were 0.19 and 0.14, respectively, with corresponding HbA1c reductions of −1.68% and −1.31% points (baseline: 9.0% and 8.9%, respectively), confirming non-inferiority and superiority of icodec.⁴⁰ In basal-only insulin-experienced individuals, overall combined level 2 or level 3 hypoglycemia rates (events/PYE) were 0.7 for icodec and 0.3 for degludec (figures 1B and 2), but were not statistically significant, with corresponding HbA1c reductions of −0.93% and −0.71% points, respectively (baseline: 8.2% and 8.1%, respectively), confirming non-inferiority and superiority of icodec.³⁰ In individuals receiving basal-bolus therapy, the overall combined level 2 or level 3 hypoglycemia rates were similar for icodec+insulin aspart versus glargine U100+insulin aspart (5.6 events/PYE (both)) (figures 1B and 2), as were the corresponding HbA1c reductions (−1.16% and −1.18% points, respectively, both from 8.3% at baseline), confirming non-inferiority of icodec.³¹

Once-weekly efsitora alfa was compared with once-daily degludec as basal-only regimens in insulin-naive and insulin-experienced individuals using various titration targets in two phase 2 trials.^{27 28} In insulin-naive individuals, the titration target for both treatments was 4.4–<5.6 mmol/L (80–100 mg/dL), while in insulin-experienced individuals, the two titration targets for efsitora were ≤7.8 mmol/L (≤140 mg/dL) (algorithm 1) and ≤6.7 mmol/L (≤120 mg/dL) (algorithm 2), and the titration target for degludec was ≤5.6 mmol/L (≤100 mg/dL).^{27 28} In insulin-experienced individuals, baseline HbA1c was reduced after 32 weeks by −0.6% point for efsitora (both titration algorithms) and −0.7% point for degludec (baseline: 8.1% for both). The rate of level 1 hypoglycemia (<3.9 mmol/L (<70 mg/dL)) was statistically significantly lower with efsitora than with degludec (23.0 vs 30.5 events/PYE; p value not reported). For level 2 hypoglycemia (<3.0 mmol/L (<54 mg/dL)), there was no statistically significant difference between arms (2.2 vs 3.0 events/PYE; p value not reported).²⁸ The difference in level 1 hypoglycemia may be attributed to the more stringent titration target used for degludec than for efsitora, resulting in statistically significantly lower fasting blood glucose with degludec than with efsitora (change from baseline: –1.8 mmol/L (–32.7 mg/dL) vs –0.9 mmol/L (–17.0 mg/dL), respectively; p value not reported). In insulin-naive individuals, however, there was no statistically significant difference between efsitora and degludec using the same titration target in terms of level 1 (3.29 vs 2.77 events/PYE, respectively) or level 2 hypoglycemia (0.22 vs 0.15 events/PYE, respectively); reductions in HbA1c were −1.20% points and −1.26% points, respectively (baseline: ~8.0%).²⁷

Discussion

This narrative review comprehensively summarizes rates of hypoglycemia from T2D treat-to-target trials of one or two times per day administered basal insulins and provides relevant context for the event rates in the ongoing or completed once-weekly insulin trials, while considering the differences in trial design, hypoglycemia definitions, basal insulin type/dose, titration targets, data collection methods and HbA1c-lowering efficacy. Our narrative approach precludes definitive conclusions to be drawn regarding the relative efficacy and safety of basal insulins as this can only be achieved using participant-level analyses of head-to-head RCT data.

Nevertheless, data indicate that, in treat-to-target RCTs, rates of hypoglycemia were generally lower with second-generation basal insulins (degludec and glargine U300) than with NPH insulin or first-generation basal insulin analogs (detemir and glargine U100) and, generally, most RCTs with basal insulin analogs reported an overall hypoglycemia rate (BG <70 mg/dL (<3.9 mmol/L) at any time of the day) of more than one event/PYE. Notably, those trials reporting lower hypoglycemic event rates had lower HbA1c reductions, well above the recommended target of <7.0%. As expected, owing to the more intensive insulin regimen, the use of mealtime bolus insulin and longer diabetes duration, hypoglycemia rates were higher in basal-bolus trials than in basal-only trials, particularly for previously insulin-naive individuals. However, the reported hypoglycemia rates were highly variable across trials, largely driven by heterogeneity in trial design, trial parameters (including eligible population), hypoglycemia definitions, glycemic control and hypoglycemia data collection methods, which can all directly impact the collection, reporting and analysis of hypoglycemia data. As these elements varied greatly across trials, it renders impossible any statistical comparison of hypoglycemia data across studies, yet holistically, these data can provide valuable clinical context when gauging hypoglycemic risk with weekly insulins relative to the ranges reported for widely used first-generation and second-generation daily basal insulin analogs.

Hypoglycemia risk is driven by a complex interplay of factors such as the use of concomitant sulfonylureas,⁸⁷ strictness of insulin titration regimens⁸⁸ and glucose-lowering efficacy, plus the strength of counter-regulatory responses which are impaired in many individuals with diabetes.⁸⁹ However, in this review, sulfonylurea usage, EOT insulin dose and the glucose-lowering efficacy of the insulins did not show consistent effects on overall hypoglycemia. Given the association between sulfonylurea usage and hypoglycemia, it was surprising that a clearer trend between the two was not seen; however, differences in other variables in the trial designs/methodologies may have had a confounding effect.

Concerns regarding greater frequency of hypoglycemia with once-weekly insulin use (icodec and efsitora) may be assuaged by contextualizing emerging once-weekly insulin data from SMBG and CGM analyses with observed hypoglycemia rates with first-generation and second-generation basal insulin analogs. Findings from this narrative review suggest that level 2 and level 3 hypoglycemia rates reported for icodec were below (in ONWARDS 1, 3, 2 and 5) or within (in ONWARDS 4) the rate ranges from basal-only (in insulin-naive and basal insulin-experienced) trials and basal-bolus insulin trials for daily-administered basal insulin analogs, respectively. Based on phase 2 data, level 2 hypoglycemia rates with efsitora were also lower than that observed with daily basal insulin analogs; however, as the phase 3 program will investigate a different titration algorithm and formulation, it remains to be seen whether these results will be replicated.

CGM is a relatively recent technological development, so for most trials included in the review, SMBG was the primary method for hypoglycemia data collection. Consequently, the detection of non-severe hypoglycemia relied on the identification of symptoms and/or self-reported BG readings, which may have underestimated actual values. The European Medicines Agency, EASD and ADA have recently recommended that CGM data be used in conjunction with participant-reported hypoglycemia outcomes as part of regulatory trials for the approval of drugs.^{90 91} In RCTs, compared with SMBG, CGM systems have demonstrated greater sensitivity in detecting hypoglycemia,^91–93 and when used to inform titration decisions, have led to reduced proportions of TBR (<3.9 mmol/L (<70 mg/dL) and <3.0 mmol/L (<54 mg/dL)) and number of hypoglycemic events.^{94 95} To date, CGM has been used in three once-weekly basal insulin studies (ONWARDS 1, 2 and 4)^{30 31 33} but it was not used for titration or insulin dose adjustments as the CGM data were blinded; future use of open CGM with titration algorithms may help to further reduce the occurrence of hypoglycemia with once-weekly basal insulin. The further use of CGM in conjunction with SMBG-based data in future trials, such as those for once-weekly basal icodec and efsitora, will provide greater clinical context and may help to identify populations at risk of hypoglycemia, facilitating the movement of clinical practice into personalized diabetes management.

This narrative review thoroughly collected data from late-phase RCTs with diverse and large sample sizes over a 22-year period. Most studies were open label with an evaluation period less than 6 months, and only 10 studies implemented a non-inferiority statistical framework. To enable more robust evaluations, based on recent FDA guidance, future studies should include an efficacy evaluation period of 6–12 months, be blinded (if possible), and include non-inferiority or superiority statistical frameworks with defined estimands.^96–98 In addition, hypoglycemia definitions need to be standardized as much as possible. Nevertheless, the data collected here can be used to provide clinical perspective on the frequency of hypoglycemia event rates in ongoing and future clinical trials assessing the safety of basal insulin analogs. A meta-analysis was not conducted due to the considerable heterogeneity in trial protocols and hypoglycemia definitions. Accordingly, only observed trends were reported without the support of statistical rigor. Additionally, the hypoglycemia rates reported here may not directly apply to routine clinical practice as some populations with severe comorbidities may have been excluded, as is typical for RCTs. Trials may have also specifically excluded individuals prone to hypoglycemia, with prior severe hypoglycemia a common exclusion criterion. It was not possible to assess hypoglycemia rates by phase (ie, initial titration vs maintenance titration) as these were not consistently reported across studies. Similarly, not all outcomes of interest were consistently reported across studies. Finally, given the emphasis on RCT data, the generalizability of our results to real-world clinical practice may be limited.

Summary

Second-generation basal insulin analogs may reduce, but not eliminate, hypoglycemia risk. Hypoglycemia rates varied widely depending on the study population, study design, insulin titration targets, insulin dosages and diabetes duration. Overall, the frequency of event rates for level 2 and level 3 hypoglycemia in most treat-to-target RCTs testing basal insulin analogs as a basal-only insulin regimen ranged from 0.06 to 7.10 events/PYE; the hypoglycemia rate for basal-bolus regimens ranged from 2.4 to 13.6 events/PYE. These rate ranges may provide a useful reference when gaging hypoglycemia risk associated with once-weekly basal insulin analogs. Most notably, although more robust comparative data are needed, this review suggests that the hypoglycemia risk data reported so far on once-weekly basal insulins are consistent with or lower than those previously reported for daily insulin basal insulin analogs despite their longer duration of action.

Acknowledgments

Footnotes

References