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

The objective of this review was to comprehensively present and summarize trends in reported rates of hypoglycemia with one or two times per day basal insulin analogs in individuals with type 2 diabetes to help address and contextualize the emerging theoretical concern of increased hypoglycemic risk with once-weekly basal insulins.Hypoglycemia data were extracted from treat-to-target randomized clinical trials conducted during 2000-2022. Published articles were identified on PubMed or within the US Food and Drug Administration submission documents. Overall, 57 articles were identified: 44 assessed hypoglycemic outcomes in participants receiving basal-only therapy (33 in insulin-naive participants; 11 in insulin-experienced participants), 4 in a mixed population (insulin-naive and insulin-experienced participants) and 9 in participants receiving basal-bolus therapy. For the analysis, emphasis was placed on level 2 (blood glucose <3.0 mmol/L (<54 mg/dL)) and level 3 (or severe) hypoglycemia.Overall, event rates for level 2 or level 3 hypoglycemia across most studies ranged from 0.06 to 7.10 events/person-year of exposure (PYE) for participants receiving a basal-only insulin regimen; the rate for basal-bolus regimens ranged from 2.4 to 13.6 events/PYE. Rates were generally lower with second-generation basal insulins (insulin degludec or insulin glargine U300) than with neutral protamine Hagedorn insulin or first-generation basal insulins (insulin detemir or insulin glargine U100). Subgroup categorization by sulfonylurea usage, end-of-treatment insulin dose or glycated hemoglobin reduction did not show consistent trends on overall hypoglycemia rates. Hypoglycemia rates reported so far for once-weekly basal insulins are consistent with or lower than those reported for daily-administered basal insulin analogs.

Keywords: Diabetes Mellitus, Type 2; Hypoglycemia; Insulin.

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 ; Hermansen et al ; Meneghini et al ; Pan et al ; Rosenstock et al ; Zinman et al 67); two BO (insulin-experienced) trials reported data for multiple basal insulins (Yki-Järvinen et al 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.

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.

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. Estimated data are reported for Goldenberg et al. 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.