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Efficacy and Tolerability of Insulin Degludec Versus Other Long-acting Basal Insulin Analogues in the Treatment of Type 1 and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis

  • Author Footnotes
    3 Zhi-Yuan Dong and Ji-Hua Feng contributed equally to the manuscript and are co–first authors.
    Zhi-Yuan Dong
    Footnotes
    3 Zhi-Yuan Dong and Ji-Hua Feng contributed equally to the manuscript and are co–first authors.
    Affiliations
    Graduate School, Guangxi Medical University, Nanning, China
    Search for articles by this author
  • Author Footnotes
    3 Zhi-Yuan Dong and Ji-Hua Feng contributed equally to the manuscript and are co–first authors.
    Ji-Hua Feng
    Footnotes
    3 Zhi-Yuan Dong and Ji-Hua Feng contributed equally to the manuscript and are co–first authors.
    Affiliations
    Graduate School, Guangxi Medical University, Nanning, China
    Search for articles by this author
  • Jian-Feng Zhang
    Correspondence
    Address correspondence to: Jian-Feng Zhang, 166 Daxuedong Road, Nanning, Guangxi, China.
    Affiliations
    Second Affiliated Hospital, Guangxi Medical University, Nanning, China
    Search for articles by this author
  • Author Footnotes
    3 Zhi-Yuan Dong and Ji-Hua Feng contributed equally to the manuscript and are co–first authors.
Open AccessPublished:October 27, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.09.012

      Abstract

      Purpose

      The goal of this study was to compare the efficacy and tolerability of insulin degludec with those of other long-acting insulin analogues (insulin glargine and insulin detemir) in patients with type 1 or 2 diabetes mellitus (T1D or T2D).

      Methods

      Those randomized controlled trials comparing insulin degludec with other long-acting insulin analogues in the treatment of patients with T1D or T2D published on or before August 21, 2022, were retrieved from PubMed, Web of Science, the Cochrane Library, and EMBASE. The efficacy end points were the changes from baseline in hemoglobin A1c and fasting plasma glucose (FPG). The tolerability end point was the prevalence of hypoglycemia confirmed throughout the treatment period.

      Findings

      Data from a total of 20 trials (19,048 patients) were included. The differences in the reductions in glycosylated hemoglobin between insulin degludec and other long-acting basal insulin analogues (insulin glargine and insulin detemir) used for the treatment of patients with T1D or T2D were not significant. However, the reduction in FPG was greater with insulin degludec (–0.370 mmol/L; 95% CI, –0.473 to –0.267 mmol/L; P ≤ 0.001). Throughout the treatment periods of all of the available trials, the estimated rate ratios of overall and nocturnal hypoglycemia were significantly decreased with insulin degludec compared with insulin glargine or insulin detemir in patients with T1D or T2D; the differences in the risks for severe hypoglycemia were not significant.

      Implications

      Compared with other long-acting insulin analogues (insulin glargine and insulin detemir), insulin degludec was associated with a significantly decreased FPG, with lower prevalences of overall and nocturnal hypoglycemia.

      Graphical abstract

      Keywords

      Introduction

      The treatment of type 1 and type 2 diabetes mellitus (T1D and T2D) requires efficient blood glucose control, especially fasting plasma glucose (FPG). Meanwhile, the risk for hypoglycemic events should be reduced to the greatest possible extent. The emergence of long-acting basal insulin analogues provides a favorable choice. Currently, the first-generation long-acting insulin analogues include insulin detemir and insulin glargine 100 U/mL (IGlar100). Compared with neutral protamine Hagedorn insulin, the first-generation long-acting insulin analogues have been associated with a longer duration of action (up to 24 hours), more stable control of FPG, and a reduced prevalence of hypoglycemia; therefore, they can serve as effective alternatives to neutral protamine Hagedorn insulin.
      • Pedersen-Bjergaard U
      • Fabricius TW
      • Thorsteinsson B.
      Synthetic long-acting insulin analogs for the management of type 1 diabetes: an update.
      However, there is still failure in basal blood glucose control and the occurrence of hypoglycemic events in the clinical treatment of diabetes mellitus, and hence a second generation of long-acting basal insulin analogues was developed (IGlar300,
      • Clements JN
      • Bello L.
      Insulin glargine 300 units/mL: A new basal insulin product for diabetes mellitus.
      insulin degludec 100 U/mL [IDeg100], and IDeg200).
      Introduction: Standards of Medical Care in Diabetes—2018.
      ,
      • Garber AJ
      • Abrahamson MJ
      • Barzilay JI.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2017 executive summary.
      Compared with other long-acting basal insulin analogues, insulin degludec has favorable pharmacokinetic and pharmacodynamic characteristics, including a long half-life of about 25 hours and a duration of action longer than 42 hours. In the stable state, the injection of insulin degludec once daily has been associated with steadily lowered blood glucose.
      • Haahr H
      • Heise T.
      A review of the pharmacological properties of insulin degludec and their clinical relevance.
      ,
      • Jonassen I
      • Havelund S
      • Hoeg-Jensen T.
      Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin.
      It has been demonstrated in previous related trials
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Philis-Tsimikas A
      • Klonoff DC
      • Khunti K.
      Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: The randomised, head-to-head CONCLUDE trial.
      that insulin degludec had hypoglycemic effects similar to those of other first- and second-generation long-acting basal insulin analogues, and meanwhile reduced the related hypoglycemic risk. In some meta-analyses, such premixed agents as insulin degludec + insulin aspart and insulin degludec + liraglutide were included.
      • Cai X
      • Gao X
      • Yang W.
      Comparison between insulin degludec/liraglutide treatment and insulin glargine/lixisenatide treatment in type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Zhang X-W
      • Zhang X-L
      • Xu B.
      Comparative safety and efficacy of insulin degludec with insulin glargine in type 2 and type 1 diabetes: a meta-analysis of randomized controlled trials.
      In this case, a meta-analysis was conducted on data from randomized, controlled trials, with all intervention measures in the included studies being insulin degludec (excluding the influence of mixed agents) and the control measures covering the first- and second-generation long-acting basal insulins, in an attempt to investigate the pros and cons of insulin degludec in hypoglycemia-related efficacy and tolerability in the treatment of most patients with T1D or T2D.

      Materials and Methods

      This meta-analysis was conducted as per the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).
      • Page MJ
      • McKenzie JE
      • Bossuyt PM.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (protocol number CRD42022300343).

      Data Sources and Retrieval

      Articles containing such key words as degludec, type 1 diabetes mellitus, type 2 diabetes mellitus, and randomized trials and published on or before August 21, 2022, were retrieved from PubMed, Web of Science, the Cochrane Library, and EMBASE. There was no restriction on language. The reference lists of relevant meeting reports and reviews were checked for further studies.

      Study Selection

      The criteria for inclusion in this systematic review and meta-analysis were: (1) randomized, controlled trials; (2) patients diagnosed with T1D or T2D; and (3) comparison of efficacy and tolerability of insulin degludec with those of insulin glargine or insulin detemir. The exclusion criteria were: (1) premixed agents of insulin degludec; and (2) short reports, letters to editors, and abstracts or minutes from scientific meetings (see Supplemental Figure S1).
      Two researchers (Z.-Y.D. and J.-H.F.) independently assessed the eligibility of studies at the heading and abstract levels; if a reference was determined to be potentially relevant, the full article was obtained for further review. Disagreements were resolved by consensus.

      End Point Measures

      The efficacy end points were the changes from baseline in hemoglobin (Hb) A1c and FPG. The tolerability end point was the prevalences of hypoglycemia (any 24-hour glucose level of ≤3.9 mmol/L), confirmed throughout the treatment period, and of overall, nocturnal (12 am to <6 am), and severe (glucose <2.9 mmol/L) hypoglycemic events, which were assessed separately.

      Data Extraction and Quality Assessment

      Two researchers (Z.-Y.D. and J.-H.F.) independently extracted the following items from each trial: number of patients, duration of follow-up, baseline characteristics, and end points of interest. Similarly, two evaluators also independently assessed the methodologic quality of all included trials using the Cochrane quality-assessment tool
      • Cumpston M
      • Li T
      • Page MJ.
      Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions.
      (see Supplemental Figure S2).

      Data Synthesis and Statistical Analysis

      The mean (SD) values of HbA1c and FPG (efficacy end points), and the estimated rate ratios (ERRs) of hypoglycemic events throughout the treatment period and the corresponding 95% CIs, were directly extracted from each trial and regarded as summary statistics. ERR was calculated, based on hypoglycemic rate, as the number of hypoglycemic events exposed per patient-year. The negative binomial regression model was adjusted based on many baseline factors. According to the degree of heterogeneity, the study estimates were combined using the fixed-effects model (Mantel-Haenszel method) or the random-effects model (DerSimonian-Laird method), and I2 statistics and Q test based on χ2 were adopted.
      • Higgins JP
      • Thompson SG
      • Deeks JJ.
      Measuring inconsistency in meta-analyses.
      The sensitivity test and meta-regression were adopted to determine the source of heterogeneity. The rate of hypoglycemic episodes (throughout the treatment period) was subjected to subgroup analysis. Funnel plots and Egger test results were adopted to assess for publication bias. P < 0.05 was considered statistically significant. The analysis was performed using Stata software versions 14.0 and 16.0 (Stata Corporation, College Station, Texas).

      Results

      Study Selection and Characteristics

      A total of 1597 references were identified from the retrieval, including 97 references to be subjected to full-text review. A total of 20 studies
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Davies MJ
      • Gross JL
      • Ono Y.
      Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: A 26-week randomized, open-label, treat-to-target non-inferiority trial.
      • Garber AJ
      • King AB
      • Del Prato S.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Gough SCL
      • Bhargava A
      • Jain R.
      Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, multinational, treat-to-target trial: The begin low volume trial.
      • Heller S
      • Buse J
      • Fisher M.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Hollander P
      • King AB
      • Del Prato S.
      Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.
      • Iwamoto Y
      • Clauson P
      • Nishida T.
      Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.
      • Lane W
      • Bailey TS
      • Gerety G.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes the SWITCH 1 randomized clinical trial.
      • Marso SP
      • McGuire DK
      • Zinman B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Onishi Y
      • Iwamoto Y
      • Yoo SJ.
      Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial.
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Philis-Tsimikas A
      • Klonoff DC
      • Khunti K.
      Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: The randomised, head-to-head CONCLUDE trial.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      • Thalange N
      • Deeb L
      • Iotova V.
      Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes.
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      • Zinman B
      • Philis-Tsimikas A
      • Cariou B.
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: A 1-year, randomized, treat-to-target trial (BEGIN Once Long).
      (19,048 patients) met the inclusion criteria and were included in the study, among which 8 included patients with T1D
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Davies MJ
      • Gross JL
      • Ono Y.
      Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: A 26-week randomized, open-label, treat-to-target non-inferiority trial.
      ,
      • Heller S
      • Buse J
      • Fisher M.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      ,
      • Iwamoto Y
      • Clauson P
      • Nishida T.
      Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.
      ,
      • Lane W
      • Bailey TS
      • Gerety G.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes the SWITCH 1 randomized clinical trial.
      ,
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      ,
      • Thalange N
      • Deeb L
      • Iotova V.
      Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes.
      and 12 included patients with T2D.
      • Garber AJ
      • King AB
      • Del Prato S.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      ,
      • Gough SCL
      • Bhargava A
      • Jain R.
      Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, multinational, treat-to-target trial: The begin low volume trial.
      ,
      • Hollander P
      • King AB
      • Del Prato S.
      Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.
      ,
      • Marso SP
      • McGuire DK
      • Zinman B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Onishi Y
      • Iwamoto Y
      • Yoo SJ.
      Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial.
      ,
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Philis-Tsimikas A
      • Klonoff DC
      • Khunti K.
      Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: The randomised, head-to-head CONCLUDE trial.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      ,
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      ,
      • Zinman B
      • Philis-Tsimikas A
      • Cariou B.
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: A 1-year, randomized, treat-to-target trial (BEGIN Once Long).
      The control measures were IGlar100,
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      ,
      • Garber AJ
      • King AB
      • Del Prato S.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Gough SCL
      • Bhargava A
      • Jain R.
      Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, multinational, treat-to-target trial: The begin low volume trial.
      • Heller S
      • Buse J
      • Fisher M.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Hollander P
      • King AB
      • Del Prato S.
      Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.
      ,
      • Lane W
      • Bailey TS
      • Gerety G.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes the SWITCH 1 randomized clinical trial.
      • Marso SP
      • McGuire DK
      • Zinman B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Onishi Y
      • Iwamoto Y
      • Yoo SJ.
      Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial.
      ,
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      ,
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      ,
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      ,
      • Zinman B
      • Philis-Tsimikas A
      • Cariou B.
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: A 1-year, randomized, treat-to-target trial (BEGIN Once Long).
      IGlar300,
      • Philis-Tsimikas A
      • Klonoff DC
      • Khunti K.
      Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: The randomised, head-to-head CONCLUDE trial.
      ,
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      and insulin detemir.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      ,
      • Davies MJ
      • Gross JL
      • Ono Y.
      Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: A 26-week randomized, open-label, treat-to-target non-inferiority trial.
      ,
      • Iwamoto Y
      • Clauson P
      • Nishida T.
      Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.
      ,
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      ,
      • Thalange N
      • Deeb L
      • Iotova V.
      Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes.
      Patients who received insulin detemir as a control were included in the T1D group, and patients who received IGlar300 as a control were included in the T2D group. The baseline characteristics of the patients from all included trials are listed in Table I, and the summary of the main results are listed in Table II. According to the Cochrane Handbook, when a single control group was used for multiple treatment groups, this was adjusted for by dividing by the number of groups treated. The control groups of the study
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      were equally divided into two groups for efficacy analysis.
      Table IBaseline characteristics of included randomized trials.
      StudyYearNo.of PatientsF/U,wkStudy PopulationInterventionControlAge, mean (SD), yFemale, %Duration of Diabetes, mean (SD), yHbA1c, mean (SD), %Baseline FPG, mean (SD), mmol/L)
      IDegControlIDegControlIDegControl
      Birkeland et al
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      201117816T1DIDeg 600 mmol/LIGlar100 + IAsp44.5 (12.7)40.422.7 (14.6)19.1 (10.8)8.4 (0.9)8.3 (0.8)9.9 (3.3)9.5 (3.8)
      IDeg 900 mmol/L45.6 (12.5)20.8 (10.6)8.5 (1.0)10.3 (4.8)
      Davies et al
      • Davies MJ
      • Gross JL
      • Ono Y.
      Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: A 26-week randomized, open-label, treat-to-target non-inferiority trial.
      201445526T1DIDeg100 + IAspIDet100 + IAsp41.3 (14.7)48.113.7 (10.6)14.4 (9.7)8.0 (1.0)8.0 (0.9)9.9 (4.0)9.5 (4.0)
      Davies et al
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      201652
      Garber et al
      • Garber AJ
      • King AB
      • Del Prato S.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      201299252T2DIDeg100 + IAsp ± Met ± PioIGlar100 + IAsp ± Met ± Pio52.9 (9.1)45.813.6 (7.4)13.4 (6.9)8.3 (0.8)8.4 (0.9)9.2 (3.0)9.2 (3.2)
      Gough et al
      • Gough SCL
      • Bhargava A
      • Jain R.
      Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, multinational, treat-to-target trial: The begin low volume trial.
      201345726T2DIDeg200 + OAD(s)IGlar100 + OAD(s)57.8 (9.0)46.88.4 (6.7)8.0 (5.6)8.3 (1.0)8.2 (0.9)9.6 (2.9)9.7 (2.6)
      Heller et al
      • Heller S
      • Buse J
      • Fisher M.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      201262952T1DIDeg100 + IAspIGlar100 + IAsp43.0 (13.6)41.519.1 (12.2)18.2 (11.4)7.7 (0.9)7.7 (1.0)9.1 (4.0)9.7 (4.4)
      Hollander et al
      • Hollander P
      • King AB
      • Del Prato S.
      Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.
      201575726T2DIDeg100 + IAsp TID ± Met ± PioIGlar100 + IAsp TID ± Met ± Pio58.9 (8.6)44.913.4 (7.2)13.7 (6.8)8.2 (0.8)8.3 (0.9)9.2 (3.0)9.2 (3.2)
      Iwamoto et al
      • Iwamoto Y
      • Clauson P
      • Nishida T.
      Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.
      2013656T1DIDeg100 + IAspIDet100 + IAsp45.5 (15.0)33.813.2 (9.1)11.8 (9.0)7.8 (0.9)7.7 (0.9)10.1 (3.7)7.9 (3.0)
      Lane et al
      • Lane W
      • Bailey TS
      • Gerety G.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes the SWITCH 1 randomized clinical trial.
      201750132T1DIDeg100 + IAspIGlar100 + IAsp45.9 (14.2)46.323.2 (13.5)23.6 (13.4)7.7 (1.0)7.5 (1.0)9.2 (4.3)9.7 (4.5)
      Marso et al
      • Marso SP
      • McGuire DK
      • Zinman B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      20177637104T2DIDeg100 + IAsp + OAD(s)IGlar100 + IAsp TID + OAD(s)65.0 (7.4)37.416.6 (8.8)16.2 (8.9)8.4 (1.6)8.4 (1.7)9.4 (3.9)9.6 (3.9)
      Mu et al
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      201756026T2DIDeg100 + MetIGlar100 + Met55.2 (9.4)47.36.7 (4.7)7.9 (5.4)8.2 (0.8)8.2 (0.9)9.2 (2.3)9.3 (2.5)
      Onishi et al
      • Onishi Y
      • Iwamoto Y
      • Yoo SJ.
      Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial.
      201343526T2DIDeg100 + OAD(s)IGlar100 + OAD(s)58.6 (9.9)46.411.8 (6.5)11.1 (6.5)8.4 (0.8)8.5 (0.8)8.4 (2.1)8.6 (1.9)
      Ono et al
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      201618626T1DIDeg100 + IAspIDet100 + IAsp48.6 (14.0)57.512.5 (9.6)12.9 (8.6)7.9 (0.9)8.2 (0.9)9.7 (3.7)9.5 (3.1)
      Pan et al
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      201683326T2DIDeg100 + MetIGlar100 + Met55.9 (9.7)49.57.6 (5.3)8.3 (5.5)8.3 (0.9)8.3 (0.8)9.4 (2.4)9.4 (2.5)
      Philis-Tsimikas et al
      • Philis-Tsimikas A
      • Klonoff DC
      • Khunti K.
      Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: The randomised, head-to-head CONCLUDE trial.
      2020160988T2DIDeg200 + OADsIGlar300 + OADs62.9 (10.0)43.615.1 (8.2)15.0 (8.4)7.6 (1.0)7.6 (0.9)7.9 (2.6)8.0 (2.6)
      Rodbard et al
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      201372552T2DIDeg100 + OAD(s)IGlar100 + OAD(s)59.7 (9.3)36.69.7 (6.3)9.0 (5.6)8.1 (0.8)8.2 (0.8)9.7 (2.4)9.5 (2.4)
      Rosenstock et al
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      201892924T2DIDeg100 + OAD(s)IGlar300 + OAD(s)60.5 (9.7)4610.5 (6.1)10.7 (6.5)8.6 (0.8)8.7 (0.8)10.1 (2.8)10.6 (2.7)
      Thalange et al
      • Thalange N
      • Deeb L
      • Iotova V.
      Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes.
      201535052T1DIDeg100 + IAspIDet100 + IAsp10.0 (4.4)44.53.9 (3.6)4.0 (3.4)8.2 (1.1)8.0 (1.1)9.0 (5.2)8.4 (4.9)
      Wysham et al
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      201772032T2DIDeg100 + OAD(s)IGlar100 + OAD(s)61.4 (10.5)46.914.2 (8.3)13.9 (8.0)7.6 (1.1)7.6 (1.1)7.7 (3.0)7.5 (2.9)
      Zinman et al
      • Zinman B
      • Philis-Tsimikas A
      • Cariou B.
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: A 1-year, randomized, treat-to-target trial (BEGIN Once Long).
      2012103052T2DIDeg100 + OAD(s)IGlar100 + OAD(s)59.3 (9.7)38.19.4 (6.3)8.6 (5.7)8.2 (0.8)8.2 (0.8)9.6 (2.6)9.7 (2.6)
      FPG = fasting plasma glucose; F/U = follow-up; Hb = hemoglobin; IAsp = insulin aspart; IDeg = insulin degludec; IDet = insulin detemir; IGlar = insulin glargine; Met = metformin; OAD = oral antidiabetic; Pio = pioglitazone; T1D = type 1 diabetes; T2D = type 2 diabetes.
      Table IISummary of the main results. Data are given as pooled effect size (95% CI) for insulin degludec versus control (insulin detemir or insulin glargine).
      ParameterT1DT2DOverall
      Change in HbA1cMD = 0.040 (−0.237 to 0.318)MD = –0.014 (–0.043 to 0.072)MD = –0.009 (–0.044 to 0.062)
      Change in FPGMD = −1.173 (−1.746 to −0.600)MD = −0.343 (−0.448 to −0.239)MD = −0.370 (−0.473 to −0.267)
      Overall hypoglycemiaERR† 
      MD = Mean Difference. †: A Poisson model with patients as a random effect; treatment, period, sequence, and dosing time as fixed effects; and logarithm of the observation time (100years) as offset was prespecified as the primary analysis to estimate the rate ratio of hypoglycemia. *P < 0.05.
      = 0.943 (0.911 to 0.975)
      ERR = 0.809 (0.762 to 0.857)ERR = 0.887 (0.835 to 0.942)
      Nocturnal hypoglycemiaERR = 0.647 (0.539 to 0.755)ERR = 0.664 (0.575 to 0.753)ERR = 0.691 (0.625 to 0.756)
      Severe hypoglycemiaERR = 0.777 (0.642 to 0.912)ERR = 0.515 (0.306 to 0.724)ERR = 0.726 (0.449 to 1.185)
      ERR = estimated rate ratios; FPG = fasting plasma glucose; Hb = hemoglobin; T1D = type 1 diabetes mellitus; T2D = type 2 diabetes mellitus.
      c MD = Mean Difference. †: A Poisson model with patients as a random effect; treatment, period, sequence, and dosing time as fixed effects; and logarithm of the observation time (100years) as offset was prespecified as the primary analysis to estimate the rate ratio of hypoglycemia. *P < 0.05.

      Efficacy End Points

      Hba1c

      For the analysis of change in HbA1c, there was a pooled analysis of data from eight studies
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      . Prior to subsequent meta-analyses, it was necessary to ensure that the baseline characteristics of the two groups were consistent (see Supplemental Figure S3).
      There was no heterogeneity in baseline HbA1c between the two groups (I2 = 0; P = 0.448 [Cochran Q test]). The fixed-effects model was combined with baseline effects to obtain a combined effect size of –0.04 (z = 1.64; P = 0.100). The baseline HbA1c values were not different between the two groups, and hence the subsequent meta-analysis could be conducted.
      As for the eight articles
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      in this subanalysis of HbA1c, on heterogeneity testing (I2 = 42.0%; P = 0.078), there was no heterogeneity among the selected articles in this study, and fixed effects could be selected (Figure 1).
      Figure 1
      Figure 1Forest plot of the effects on hemoglobulin A1c of treatment with insulin degludec versus control (insulin detemir or insulin glargine) in patients with type 1 and type 2 diabetes mellitus. WMD = weighted mean difference.
      The combined effect size was –0.009 (–0.044 to 0.062), which was not significant (z = 0.33; P = 0.739). The difference in HbA1c between the intervention group and the control group after treatment was not significant.

      FPG

      In the analysis of the change from baseline in FPG, there was a pooled analysis of data from nine studies
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Marso SP
      • McGuire DK
      • Zinman B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      . Prior to subsequent meta-analysis, it was necessary to ensure that the baseline characteristics of the two groups were consistent (see Supplemental Figure S4).
      There was no heterogeneity in baseline FPG between the two groups (I2 = 32.5%; P = 0.139). The fixed-effects model was combined with baseline effects to obtain a combined effect size of –0.081 mmol/L (z = 1.36; P = 0.173), indicating that the difference in baseline FPG between the two groups was not significant.
      As for the nine articles
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Marso SP
      • McGuire DK
      • Zinman B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      in this subanalysis of FPG, on heterogeneity testing (I2 = 44.5%; P = 0.055), there was no heterogeneity among the selected articles, and fixed effects could be selected (Figure 2).
      Figure 2
      Figure 2Forest plot of the effects on fasting plasma glucose of treatment with insulin degludec versus control (insulin detemir or insulin glargine) in patients with type 1 and type 2 diabetes mellitus. WMD = weighted mean difference.
      The combined effect size was –0.370 (–0.473 to –0.267), which was significant (z = 7.05; P < 0.001). Compared with that in the control group, the FPG in the intervention group was significantly lower (by 0.37 mmol/L), indicating that the intervention effect was significant.

      Tolerability End Points

      All Confirmed Hypoglycemia

      As for the 19 articles
      • Birkeland KI
      • Home PD
      • Wendisch U.
      Insulin degludec in type 1 diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.
      • Davies M
      • Sasaki T
      • Gross JL.
      Comparison of insulin degludec with insulin detemir in type 1 diabetes: A 1-year treat-to-target trial.
      • Davies MJ
      • Gross JL
      • Ono Y.
      Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: A 26-week randomized, open-label, treat-to-target non-inferiority trial.
      • Garber AJ
      • King AB
      • Del Prato S.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Gough SCL
      • Bhargava A
      • Jain R.
      Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, multinational, treat-to-target trial: The begin low volume trial.
      • Heller S
      • Buse J
      • Fisher M.
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Hollander P
      • King AB
      • Del Prato S.
      Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.
      • Iwamoto Y
      • Clauson P
      • Nishida T.
      Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.
      • Lane W
      • Bailey TS
      • Gerety G.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes the SWITCH 1 randomized clinical trial.
      • Mu YM
      • Guo LX
      • Li L.
      [The efficacy and safety of insulin degludec versus insulin glargine in insulin-naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial].
      • Onishi Y
      • Iwamoto Y
      • Yoo SJ.
      Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial.
      • Ono Y
      • Nishida T
      • Hyllested-Winge J.
      A comparison of IDeg.
      • Pan C
      • Gross JL
      • Yang W.
      A multinational, randomized, open-label, treat-to-target trial comparing insulin degludec and insulin glargine in insulin-naïve patients with type 2 diabetes mellitus.
      • Philis-Tsimikas A
      • Klonoff DC
      • Khunti K.
      Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: The randomised, head-to-head CONCLUDE trial.
      • Rodbard HW
      • Cariou B
      • Zinman B.
      Comparison of insulin degludec with insulin glargine in insulin-naive subjects with type 2 diabetes: A 2-year randomized, treat-to-target trial.
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      • Thalange N
      • Deeb L
      • Iotova V.
      Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes.
      • Wysham C
      • Bhargava A
      • Chaykin L.
      Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes the SWITCH 2 randomized clinical trial.
      • Zinman B
      • Philis-Tsimikas A
      • Cariou B.
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: A 1-year, randomized, treat-to-target trial (BEGIN Once Long).
      in the subanalysis of hypoglycemia, on heterogeneity testing (I2 = 52.2%; P = 0.004), there was statistically significant heterogeneity among the selected articles in this study. Furthermore, on the star plot, there was a strong possibility of heterogeneity in some articles (see Supplemental Figure S5).
      There was low heterogeneity among these articles; therefore, random effects could be used (Natural logarithm ERR (LnERR) = –0.12; 95% CI, –0.18 to –0.06). The combined effect size was obtained after conversion (ERR = 0.887; 95% CI, 0.835 to 0.942; z = 3.7; P < 0.001). In the treatment of T1D and T2D, the overall prevalence of hypoglycemia with insulin degludec was 88.7% of that in the control group, suggesting that the prevalence of all confirmed hypoglycemia was lower with insulin degludec than with other long-acting insulin analogues.

      Nocturnal Hypoglycemia

      As for the 20 articles in the subanalysis of nocturnal hyperglycemia, the heterogeneity test result was I2 = 48.7% and the Cochran Q test result was P < 0.1. Furthermore, on the star plot, there was a strong possibility of heterogeneity in some articles (see Supplemental Figure S6). It can be concluded that there was low heterogeneity among these articles in the study, and random effects could be selected (Figure 3).
      Figure 3
      Figure 3Forest plot of the effects on nocturnal hypoglycemia of treatment with insulin degludec versus control (insulin detemir or insulin glargine) in patients with type 1 and type 2 diabetes mellitus. ES (LnERR) = Effect Size.
      The effect size was combined with random effects (LnERR = –0.37; 95% CI, –0.47 to –0.28); the combined effect size was obtained after conversion (ERR = 0.691; 95% CI, 0.625 to 0.756) was statistically significant (z = 7.54; P < 0.001), thus indicating that the prevalence of nocturnal hypoglycemia in the insulin degludec treatment group was 69.1% of that in the control group, meaning that the prevalence of nocturnal hypoglycemia was lower with insulin degludec than with other long-acting insulin analogues.

      Severe Hypoglycemia

      As for the 12 articles in the subanalysis of severe hypoglycemia, the heterogeneity test result was I2 = 63.2% and the Cochran Q test result was P < 0.1, which indicated moderate heterogeneity among the selected articles. Furthermore, on the star plot, there was a strong possibility of heterogeneity in some articles (see Supplemental Figure S7). The random-effects model could be selected to combine the effect size (Figure 4).
      Figure 4
      Figure 4Forest plot of the effects on severe hypoglycemia of treatment with insulin degludec versus control (insulin detemir or insulin glargine) in patients with type 1 and type 2 diabetes mellitus. ES (LnERR) = Effect Size.
      The effect size was LnERR = –0.32 (95% CI, –0.80 to 0.17), while after conversion the ERR = 0.726 (95% CI, 0.449 to 1.185), which did not reach statistical significance (z = 1.28; P = 0.199), thus indicating that the prevalence of severe hypoglycemia in the insulin degludec treatment group was 72.6% of that in the control group, with no statistical significance. Therefore, the difference in the prevalences of severe hypoglycemia between the insulin degludec treatment group and the control group was not significant.

      Analyses by Diabetes Subgroup

      The patients in these studies were stratified by diabetes type, namely the T1D group and the T2D group.

      T1D Group

      Efficacy

      HbA1c. There was moderate heterogeneity in the T1D group (I2 = 71.5%; P = 0.015). The random-effects model was selected to combine the effect size to obtain a combined effect size of 0.040 (95% CI, –0.237 to 0.318). In the treatment of patients with TD1, the decrease in HbA1c with insulin degludec was not statistically significant (z = 0.28; P = 0.776).
      On the Egger test (P = 0.288) and the Begg test (P = 0.308), there was no publication bias in the T1D group.
      FPG. There was no heterogeneity in the T1D group (I2 = 9.2%; P = 0.347). The fixed-effects model was selected to obtain a combined effect size of –1.173 (95% CI, –1.746 to –0.600). In the treatment of patients with T1D, the decrease in FPG was statistically significant (by 1.173 mmol/L) with insulin degludec (z = 4.01; P < 0.001).
      On the Egger test (P = 0.695) and the Begg test (P = 0.734), there was no publication bias in the T1D group.

      Tolerability

      All Confirmed Hypoglycemia. The heterogeneity in the T1D group was not statistically significant (I2 = 0; P = 0.520). The fixed-effects model was selected to combine the effect size, obtaining an ERR = 0.943 (95% CI, 0.911 to 0.975). In the treatment of patients with T1D, the overall prevalence of hypoglycemia with insulin degludec was 94.3% of that in the control group, which was statistically significant (z = 3.20; P < 0.001) (Figure 5).
      Figure 5
      Figure 5Forest plot of the effects on all confirmed hypoglycemia of treatment with insulin degludec versus control (insulin detemir) in patients with type 1 and type 2 diabetes mellitus. ES (LnERR) = Effect Size.
      The bias test was conducted based on subgroups, and the funnel plot was plotted (see Supplemental Figure S8). On the Egger test (P = 0.861) and the Begg test (P = 0.208), there was no publication bias in the T1D group.
      Nocturnal Hypoglycemia. There was moderate heterogeneity of T1D group (I2 = 61.7%; P = 0.007). The random-effects model was selected (ERR = 0.647; 95% CI, 0.539 to 0.755). In the treatment of patients with T1D, the prevalence of nocturnal hypoglycemia with insulin degludec was 64.7% of that in the control group, which was statistically significant (z = 5.16; P < 0.001).
      The bias test was conducted based on subgroups, and the funnel plot was plotted (see Supplemental Figure S9). On the Egger test (P = 0.101) and the Begg test (P = 0.076), there was no publication bias in the T1D group.
      Severe Hypoglycemia. There was no heterogeneity of the T1D group (I2 = 0; P = 0.547). The fixed-effects model was selected (ERR = 0.777; 95% CI, 0.642 to 0.912). In the treatment of patients with T1D, the prevalence of severe hypoglycemia with insulin degludec was 77.7% of that in the control group, with no statistical significance (z = 0.60; P = 0.552).
      On the Egger test (P = 0.064) and the Begg test (P = 0.221), there was no publication bias in the T1D group.

      T2D Group

      Efficacy

      HbA1c. There was no heterogeneity of the T2D group (I2 = 0; P = 0.447). The fixed-effects model was selected, obtaining a combined effect size of –0.014 (–0.043 to 0.072). In the treatment of patients with T2D, the HbA1c with insulin degludec had no statistical significance (z = 0.50; P = 0.621).
      On the Egger test (P = 0.850) and the Begg test (P = 0.707), there was no publication bias in the T2D group.
      FPG. There was no heterogeneity of the T2D group (I2 = 13.4%; P = 0.328). The fixed-effects model was selected, obtaining a combined effect size of –0.343 (–0.448 to –0.239). In the treatment of patients with T2D, the FPG with insulin degludec was significantly lower, by 0.343 mmol/L, which was statistically significant (z = 6.43; P < 0.001).
      On the Egger test (P = 0.259) and the Begg test (P = 0.133), there was no publication bias in the T2D group.

      Tolerability

      All Confirmed Hypoglycemia. The heterogeneity of the T2D group (I2 = 15.7%; P = 0.294) was not statistically significant. The fixed-effects model was selected to combine the effect size, obtaining an ERR = 0.809 (95% CI, 0.762 to 0.857). In the treatment of patients with T2D, the overall prevalence of hypoglycemia with insulin degludec was 80.9% of that in the control group, which was statistically significant (z = 6.58; P < 0.001) (Figure 5).
      The bias test was conducted based on subgroups, and the funnel plot was plotted (see Supplemental Figure S8). On the Egger test (P = 0.578) and the Begg test (P = 0.755), there was no publication bias in the T2D group.
      Nocturnal Hypoglycemia. There was mild heterogeneity of the T2D group (I2 = 37.9%; P = 0.088). The random-effects model was selected (ERR = 0.664; 95% CI, 0.575 to 0.753). In the treatment of patients with T2D, the prevalence of nocturnal hypoglycemia with insulin degludec was 66.4% of that in the control group, which was statistically significant (z = 5.05; P < 0.001).
      The bias test was conducted based on subgroups, and the funnel plot was plotted (see Supplemental Figure S9). On the Egger test (P = 0.348) and the Begg test (P = 0.373), there was no publication bias in the T2D group.
      Severe Hypoglycemia. There was moderate heterogeneity of the T2D group (I2 = 66.2%; P = 0.007). The random-effects model was selected to combine the effect size, obtaining an ERR = 0.515 (95% CI, 0.306 to 0.724). In the treatment of patients with T2D, the prevalence of severe hypoglycemia with insulin degludec was 51.5% of that in the control group, with no statistical significance (z = 1.23; P = 0.218).
      On the Egger test (P = 0.487) and the Begg test (P = 0.368), there was no publication bias in the T2D group.

      Sensitivity Analysis

      Sensitivity analysis performed for both the efficacy and tolerability analyses indicated no study significantly influencing the heterogeneity.

      Discussion

      The following conclusions can be drawn from this meta-analysis. First, insulin degludec was associated with effective reductions in the overall and nocturnal prevalences of hypoglycemia in the T1D and T2D groups throughout the treatment period. Second, the differences in the prevalences of severe hypoglycemia were not significant between the group treated with insulin degludec and those treated with other long-acting basal insulin analogues throughout the treatment period. Third, insulin degludec was associated with greater reductions in FPG after treatment. Fourth, the difference in the control of HbA1c between treatment with insulin degludec and that with other long-acting basal insulin analogues was not significant.
      The T1D group included all patients from all studies of insulin detemir as a control measure, and the T2D group included all patients from all studies of IGlar300 as a control measure. The following conclusions can be drawn from the analysis of the T1D and T2D subgroups. In the treatment of T1D, insulin degludec was associated with a significantly lower FPG, and lower prevalences of overall and nocturnal hypoglycemia, compared with the first generation of long-acting basal insulin analogues (insulin detemir and IGlar100). In the treatment of T2D, insulin degludec was associated with significantly lower FPG and prevalences of overall and nocturnal hypoglycemia compared with first- and second-generation insulin glargine (IGlar100 and IGlar300).
      Compared with other meta-analyses,
      • Zhang X-W
      • Zhang X-L
      • Xu B.
      Comparative safety and efficacy of insulin degludec with insulin glargine in type 2 and type 1 diabetes: a meta-analysis of randomized controlled trials.
      ,
      • Liu W
      • Yang X
      • Huang J.
      Efficacy and Safety of Insulin Degludec versus Insulin Glargine: A Systematic Review and Meta-Analysis of Fifteen Clinical Trials.
      the present study had some advantages. First, more participants and trials were included in this meta-analysis, (20 studies, 19,048 patients). Second, patients with T1D and T2D were included, which covers >95% of diabetic patients,
      • Saeedi P
      • Petersohn I
      • Salpea P.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.
      thus providing an extensive basis for the efficacy and tolerability assessments of insulin degludec in the treatment of diabetes mellitus. Third, the first- and second-generation long-acting basal insulin analogues were included as control measures, providing a comprehensive basis for the comparison of efficacy and tolerability between insulin degludec and other long-acting basal insulin analogues. Fourth, pure insulin degludec agents were selected as intervention measures in all included studies, free from the influence of premixed agents as intervention measures on efficacy and tolerability.
      It was found that, throughout the treatment period, the overall and nocturnal prevalences of hypoglycemia in the insulin degludec treatment group were relatively low, and that the prevalence of severe hypoglycemia in the test group was similar to that in the control group. These findings indicate that severe hypoglycemia may occur in the daytime during treatment and that the occurrence of severe hypoglycemia can be caused by other hypoglycemic measures during treatment. For example, combined treatment with a long-acting basal insulin analogue plus mealtime insulin aspart may induce postprandial hypoglycemia or even severe hypoglycemia. There was a similar situation in the efficacy assessment. After treatment with insulin degludec, FPG was reduced more effectively, but efficacy with regard to HbA1c control was similar to that in the control group. HbA1c reflects the overall control of blood glucose over a certain period of time, including the control of basal blood glucose, postprandial blood glucose, and hypoglycemia. It was demonstrated that other hypoglycemic measures and long-acting basal insulin analogues in the included studies were also involved in the effective control of HbA1c, and may even exert a stronger impact on this control, while other hypoglycemic measures are less involved in the control of FPG, which can better reflect the efficacy of long-acting basal insulin analogues.
      There were some limitations in this study. First, there were many control measures included. For example, various oral hypoglycemic drugs and short-acting insulin were used in combination during treatment, which inevitably caused some clinical heterogeneity. Second, there was a lack of exploration on IGlar300 among the control measures in the included studies, and in particular there was none in the T1D trials. It has been reported in some controlled trials that IGlar300 was associated with better tolerability,
      • Rosenstock J
      • Cheng A
      • Ritzel R.
      More similarities than differences testing insulin glargine 300 units/mL versus insulin degludec 100 units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial.
      and more studies are required to further verify the pros and cons of the second-generation long-acting insulin analogues. Third, in most cases, heterogeneity could not be explained by subgroup analysis or results analysis. Insulin detemir, insulin glargine, and insulin aspart in the control groups were selected successively for subgroup regression analysis, but no source of heterogeneity was found; the source of heterogeneity was found only in the analysis of overall hypoglycemia by type of diabetes, and hence the random-effects model was adopted. Fourth, weight gain as part of the evaluation of insulin tolerability was not included in this analysis because most of the articles lacked raw data.

      Conclusions

      Compared with other long-acting insulin analogues (insulin glargine and insulin detemir), insulin degludec was associated with significantly decreased FPG, with lower prevalences of overall and nocturnal hypoglycemia. In the treatment of T1D, FPG and the prevalences of overall and nocturnal hypoglycemia were significantly lower with insulin degludec compared with the first generation of long-acting basal insulin analogues (insulin detemir and IGlar100). In the treatment of T2D, FPG and the prevalences of overall and nocturnal hypoglycemia were significantly lower with insulin degludec compared with first- and second-generation insulin glargine (IGlar100 and IGlar300).

      DECLARATION OF INTEREST

      The authors have indicated that they have no conflicts of interest with regard to the content of this article.

      Acknowledgments

      We thank Dr. Jian-Feng Zhang's team members Rui-Qi Yang, Huan Wan and Wei Chen for their comments.

      Sources of funding

      The work was supported by the High-level Medical Expert Training Program of Guangxi "139" Plan Funding (No. G201903027), and the funders had no role in a conflict of interest.

      Author Contributions

      Zhi-Yuan Dong: Conceptualization, Software, Literature Search and Screening, Data Collection and Interpretation, Methodologic Quality, Figure and Table Generation, Writing - Original Draft; Ji-Hua Feng: Literature Screening, Data Collection and Curation, Methodologic Quality, Writing - Original Draft; Jian-Feng Zhang (Corresponding Author): Conceptualization, Funding Acquisition, Resources, Supervision, Writing - Review & Editing. Zhi-Yuan Dong and Ji-Hua Feng contributed equally to the manuscript.

      Appendix. Supplementary materials

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